ncRNA AND USES THEREOF

ABSTRACT

The present invention relates to compositions and methods for cancer diagnosis, research and therapy, including but not limited to, cancer markers. In particular, the present invention relates to ncRNAs as diagnostic markers and clinical targets for prostate, lung, breast and pancreatic cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.13/299,000 filed Nov. 17, 2011, which claims priority to U.S.Provisional Application No. 61/415,490, filed Nov. 19, 2010, each ofwhich are herein incorporated by referenced in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under CA111275 awardedby the National Institutes of Health and @81XWH-08-1-0031 and@81XWH-11-1-0520 awarded by the U.S. Army Medical Research and MaterielCommand. The government has certain rights in the invention.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for cancerdiagnosis, research and therapy, including but not limited to, cancermarkers. In particular, the present invention relates to ncRNAs asdiagnostic markers and clinical targets for prostate, lung, breast andpancreatic cancer.

BACKGROUND OF THE INVENTION

A central aim in cancer research is to identify altered genes that arecausally implicated in oncogenesis. Several types of somatic mutationshave been identified including base substitutions, insertions,deletions, translocations, and chromosomal gains and losses, all ofwhich result in altered activity of an oncogene or tumor suppressorgene. First hypothesized in the early 1900's, there is now compellingevidence for a causal role for chromosomal rearrangements in cancer(Rowley, Nat Rev Cancer 1: 245 (2001)). Recurrent chromosomalaberrations were thought to be primarily characteristic of leukemias,lymphomas, and sarcomas. Epithelial tumors (carcinomas), which are muchmore common and contribute to a relatively large fraction of themorbidity and mortality associated with human cancer, comprise less than1% of the known, disease-specific chromosomal rearrangements (Mitelman,Mutat Res 462: 247 (2000)). While hematological malignancies are oftencharacterized by balanced, disease-specific chromosomal rearrangements,most solid tumors have a plethora of non-specific chromosomalaberrations. It is thought that the karyotypic complexity of solidtumors is due to secondary alterations acquired through cancer evolutionor progression.

Two primary mechanisms of chromosomal rearrangements have beendescribed. In one mechanism, promoter/enhancer elements of one gene arerearranged adjacent to a proto-oncogene, thus causing altered expressionof an oncogenic protein. This type of translocation is exemplified bythe apposition of immunoglobulin (IG) and T-cell receptor (TCR) genes toMYC leading to activation of this oncogene in B- and T-cellmalignancies, respectively (Rabbitts, Nature 372: 143 (1994)). In thesecond mechanism, rearrangement results in the fusion of two genes,which produces a fusion protein that may have a new function or alteredactivity. The prototypic example of this translocation is the BCR-ABLgene fusion in chronic myelogenous leukemia (CML) (Rowley, Nature 243:290 (1973); de Klein et al., Nature 300: 765 (1982)). Importantly, thisfinding led to the rational development of imatinib mesylate (Gleevec),which successfully targets the BCR-ABL kinase (Deininger et al., Blood105: 2640 (2005)). Thus, diagnostic methods that specifically identifyepithelial tumors are needed.

SUMMARY OF THE INVENTION

The present invention relates to compositions and methods for cancerdiagnosis, research and therapy, including but not limited to, cancermarkers. In particular, the present invention relates to ncRNAs asdiagnostic markers and clinical targets for cancer (e.g., prostate,lung, breast and pancreatic cancer).

Embodiments of the present invention provide compositions, kits, andmethods useful in the detection and screening of a cancer. Experimentsconducted during the course of development of embodiments of the presentinvention identified upreguation of one or more non-coding RNAs incancer. Some embodiments of the present invention provide compositionsand methods for detecting expression levels of such ncRNAs.Identification of ncRNAs finds use in screening, diagnostic and researchuses.

For example, in some embodiments, the present invention provides amethod of screening for the presence of a cancer in a subject,comprising contacting a biological sample from a subject with a reagentfor detecting the level of expression of one or more non-coding RNAs(ncRNA); and detecting the level of expression of the ncRNA in thesample, wherein an increased level of expression of the ncRNA in thesample is indicative of a cancer in the subject. In some embodiments,the cancer is a prostate cancer. In some instances, the increased levelof expression of the ncRNA in the sample is relative to the level ofncRNA in a control sample. The control sample may comprise one or morenormal cells. In some instances, the normal cells are normal prostatecells. In other instances, the increased level of expression of thencRNA in the sample is relative to the level of expression of the ncRNAin a sample from a prior time point. Alternatively, the increased levelof expression of the ncRNA in the sample is relative to apre-established threshold level. In some embodiments, the ncRNAs aredescribed by SEQ ID NOs: 1-9. In some embodiments, the non-coding RNAscomprise one or more PCAT transcripts. In some embodiments, thenon-coding RNAs are selected from the group comprising PCAT1, PCAT14,PCAT43 and PCAT 109. In some embodiments, the sample is tissue, blood,plasma, serum, urine, urine supernatant, urine cell pellet, semen,prostatic secretions or prostate cells. In some instances, detecting thelevel of expression of the ncRNA comprises one or more in vitro assays.In some embodiments, the detection is carried out utilizing a sequencingtechnique, a nucleic acid hybridization technique, a nucleic acidamplification technique, or an immunoassay. However, the invention isnot limited to the technique employed. In some embodiments, the nucleicacid amplification technique is polymerase chain reaction, reversetranscription polymerase chain reaction, transcription-mediatedamplification, ligase chain reaction, strand displacement amplificationor nucleic acid sequence based amplification. In some embodiments, theprostate cancer is localized prostate cancer or metastatic prostatecancer. In some embodiments, the reagent is a pair of amplificationoligonucleotides or an oligonucleotide probe.

Additional embodiments provide a method of screening for the presence ofa cancer in a subject, comprising contacting a biological sample from asubject with a reagent for detecting the level of expression of two ormore (e.g., 10 or more, 25 or more, 50 or more, 100 or more or all 121)non-coding RNAs (ncRNA); and detecting the level of expression of thencRNA in the sample, wherein an increased level of expression of thencRNA in the sample is indicative of cancer in the subject. In someembodiments, the cancer is a prostate cancer. In some instances, theincreased level of expression of the ncRNA in the sample is relative tothe level of ncRNA in a control sample. The control sample may compriseone or more normal cells. In some instances, the normal cells are normalprostate cells. In other instances, the increased level of expression ofthe ncRNA in the sample is relative to the level of expression of thencRNA in a sample from a prior time point. Alternatively, the increasedlevel of expression of the ncRNA in the sample is relative to apre-established threshold level. In some embodiments, at least one ofthe two or more ncRNAs are selected from a group comprising PCAT1,PCAT2, PCAT3, PCAT4, PCAT5, PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11,PCAT12, PCAT13, PCAT14, PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20,PCAT21, PCAT22, PCAT23, PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29,PCAT30, PCAT31, PCAT32, PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38,PCAT39, PCAT40, PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47,PCAT48, PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56,PCAT57, PCAT58, PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64, PCAT65,PCAT66, PCAT67, PCAT68, PCAT69, PCAT70, PCAT71, PCAT72, PCAT73, PCAT74,PCAT75, PCAT76, PCAT77, PCAT78, PCAT79, PCAT80, PCAT81, PCAT82, PCAT83,PCAT84, PCAT85, PCAT86, PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92,PCAT93, PCAT94, PCAT95, PCAT96, PCAT97, PCAT98, PCAT99, PCAT100,PCAT101, PCAT102, PCAT103, PCAT104, PCAT105, PCAT106, PCAT107, PCAT108,PCAT109, PCAT110, PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116,PCAT117, PCAT118, PCAT119, PCAT120, and PCAT121. In some embodiments,the two or more ncRNAs are selected from the group comprising PCAT1,PCAT2, PCAT3, PCAT4, PCAT5, PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11,PCAT12, PCAT13, PCAT14, PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20,PCAT21, PCAT22, PCAT23, PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29,PCAT30, PCAT31, PCAT32, PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38,PCAT39, PCAT40, PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47,PCAT48, PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56,PCAT57, PCAT58, PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64, PCAT65,PCAT66, PCAT67, PCAT68, PCAT69, PCAT70, PCAT71, PCAT72, PCAT73, PCAT74,PCAT75, PCAT76, PCAT77, PCAT78, PCAT79, PCAT80, PCAT81, PCAT82, PCAT83,PCAT84, PCAT85, PCAT86, PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92,PCAT93, PCAT94, PCAT95, PCAT96, PCAT97, PCAT98, PCAT99, PCAT100,PCAT101, PCAT102, PCAT103, PCAT104, PCAT105, PCAT106, PCAT107, PCAT108,PCAT109, PCAT110, PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116,PCAT117, PCAT118, PCAT119, PCAT120, and PCAT121. In some instances,detecting the level of expression of the ncRNA comprises one or more invitro assays.

Further embodiments of the present invention provide an array,comprising reagents for detecting the level of expression of two or more(e.g., 10 or more, 25 or more, 50 or more, 100 or more or all 121)non-coding RNAs (ncRNA) selected from, for example, PCAT1, PCAT2, PCAT3,PCAT4, PCAT5, PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11, PCAT12,PCAT13, PCAT14, PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20, PCAT21,PCAT22, PCAT23, PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29, PCAT30,PCAT31, PCAT32, PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38, PCAT39,PCAT40, PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47, PCAT48,PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56, PCAT57,PCAT58, PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64, PCAT65, PCAT66,PCAT67, PCAT68, PCAT69, PCAT70, PCAT71, PCAT72, PCAT73, PCAT74, PCAT75,PCAT76, PCAT77, PCAT78, PCAT79, PCAT80, PCAT81, PCAT82, PCAT83, PCAT84,PCAT85, PCAT86, PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92, PCAT93,PCAT94, PCAT95, PCAT96, PCAT97, PCAT98, PCAT99, PCAT100, PCAT101,PCAT102, PCAT103, PCAT104, PCAT105, PCAT106, PCAT107, PCAT108, PCAT109,PCAT110, PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116, PCAT117,PCAT118, PCAT119, PCAT120, or PCAT121. In some embodiments, the reagentis a pair of amplification oligonucleotides or an oligonucleotide probe.

In some embodiments, the present invention provides a method forscreening for the presence of a cancer in a subject, comprisingcontacting a biological sample from a subject with a reagent fordetecting the level of expression of one or more non-coding RNAs; anddetecting the level of expression of the ncRNA in the sample, wherein anincreased level of expression of the ncRNA in the sample is indicativeof cancer in the subject. In some instances, the cancer is a lungcancer. In some instances, the increased level of expression of thencRNA in the sample is relative to the level of ncRNA in a controlsample. The control sample may comprise one or more normal cells. Insome instances, the normal cells are normal lung cells. In otherinstances, the increased level of expression of the ncRNA in the sampleis relative to the level of expression of the ncRNA in a sample from aprior time point. Alternatively, the increased level of expression ofthe ncRNA in the sample is relative to a pre-established thresholdlevel. In some instances, the one or more non-coding RNAs are selectedfrom the group comprising M41 and ENST-75. In some instances, detectingthe level of expression of the ncRNA comprises one or more in vitroassays.

In some embodiments, the present invention provides a method forscreening for the presence of a cancer in a subject, comprisingcontacting a biological sample from a subject with a reagent fordetecting the level of expression of one or more non-coding RNAs; anddetecting the level of expression of the ncRNA in the sample, wherein anincreased level of expression of the ncRNA in the sample is indicativeof cancer in the subject. In some instances, the cancer is a breastcancer. In some instances, the increased level of expression of thencRNA in the sample is relative to the level of ncRNA in a controlsample. The control sample may comprise one or more normal cells. Insome instances, the normal cells are normal breast cells. In otherinstances, the increased level of expression of the ncRNA in the sampleis relative to the level of expression of the ncRNA in a sample from aprior time point. Alternatively, the increased level of expression ofthe ncRNA in the sample is relative to a pre-established thresholdlevel. In some instances, the one or more ncRNAs are selected from thegroup comprising TU0011194, TU0019356 and TU0024146. In some instances,detecting the level of expression of the ncRNA comprises one or more invitro assays.

In some embodiments, the present invention provides a method forscreening for the presence of cancer in a subject, comprising contactinga biological sample from a subject with a reagent for detecting thelevel of expression of one or more non-coding RNAs; and detecting thelevel of expression of the ncRNA in the sample, wherein an increasedlevel of expression of the ncRNA in the sample is indicative of cancerin the subject. In some instances, the cancer is a pancreatic cancer. Insome instances, the increased level of expression of the ncRNA in thesample is relative to the level of ncRNA in a control sample. Thecontrol sample may comprise one or more normal cells. In some instances,the normal cells are normal pancreatic cells. In other instances, theincreased level of expression of the ncRNA in the sample is relative tothe level of expression of the ncRNA in a sample from a prior timepoint. Alternatively, the increased level of expression of the ncRNA inthe sample is relative to a pre-established threshold level. In someinstances, the one or more ncRNAs are selected from the group comprisingTU0011194, TU0019356 and TU0024146. In some instances, detecting thelevel of expression of the ncRNA comprises one or more in vitro assays.

In still further embodiments, the present invention provides a method ofscreening for the presence of a cancer in a subject, comprising (a)contacting a biological sample from a subject with a gene expressiondetection assay, wherein the gene expression detection assay comprises agene expression informative reagent for identification of the level ofexpression of SChLAP-1; (b) detecting the level of expression ofSChLAP-1 in the sample; and (c) diagnosing cancer in the subject when anincreased level of expression of SChLAP-1 in the sample is detected. Insome instances, the cancer is a prostate cancer. In some instances, theincreased level of expression of SChLAP-1 in the sample is relative tothe level of SChLAP-1 in a control sample. The control sample maycomprise one or more normal cells. In some instances, the normal cellsare normal prostate cells. In other instances, the increased level ofexpression of SChLAP-1 in the sample is relative to the level ofexpression of SChLAP-1 in a sample from a prior time point.Alternatively, the increased level of expression of SChLAP-1 in thesample is relative to a pre-established threshold level. In someinstances, detecting the level of expression of SChLAP-1 comprises oneor more in vitro assays. In some instances, the gene expressiondetection assay further comprises a gene expression informative reagentfor identification of the level of expression of one or more ncRNAs.

In additional embodiments, the present invention provides a method ofidentifying subjects at risk of cancer metastatis, comprising (a)contacting a biological sample from a subject with a gene expressiondetection assay, wherein the gene expression detection assay comprises agene expression informative reagent for identification of the level ofexpression of SChLAP-1; (b) detecting the level of expression ofSChLAP-1 in the sample using an in vitro assay; and (c)

identifying subjects at risk of cancer metastasis when an increasedlevel of expression of SChLAP-1 in the sample is detected. In someembodiments, the subject is at increased risk of lethal prostate cancerwhen an increased level of expression of SChLAP-1 in the sample isdetected. In some instances, the cancer is a prostate cancer. In someinstances, the increased level of expression of SChLAP-1 in the sampleis relative to the level of SChLAP-1 in a control sample. The controlsample may comprise one or more normal cells. In some instances, thenormal cells are normal prostate cells. In other instances, theincreased level of expression of SChLAP-1 in the sample is relative tothe level of expression of SChLAP-1 in a sample from a prior time point.Alternatively, the increased level of expression of SChLAP-1 in thesample is relative to a pre-established threshold level. In someinstances, detecting the level of expression of SChLAP-1 comprises oneor more in vitro assays. In some instances, the gene expressiondetection assay further comprises a gene expression informative reagentfor identification of the level of expression of one or more ncRNAs.

Disclosed herein may be methods, systems, compositions and kits foranalyzing, diagnosing, prognosing, monitoring, and/or treating a cancer.Such systems may comprise (a) a probe set may comprise a plurality ofprobes, wherein the plurality of probes may comprise a sequence thathybridizes to at least a portion of one or more target moleculesselected from the group may comprise PCAT, SChLAP-1, TU0011194,TU0019356, TU0024146, TU0009141, TU0062051, TU0021861, M41, ENST-75, andSEQ ID NOs: 1-9; and (b) a computer model or algorithm for analyzing anexpression level and/or expression profile of a target moleculehybridized to the probe in a sample from a subject suffering from acancer. The PCAT may be selected from the group may comprise PCAT1,PCAT2, PCAT3, PCAT4, PCAT5, PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11,PCAT12, PCAT13, PCAT14, PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20,PCAT21, PCAT22, PCAT23, PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29,PCAT30, PCAT31, PCAT32, PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38,PCAT39, PCAT40, PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47,PCAT48, PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56,PCAT57, PCAT58, PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64, PCAT65,PCAT66, PCAT67, PCAT68, PCAT69, PCAT70, PCAT71, PCAT72, PCAT73, PCAT74,PCAT75, PCAT76, PCAT77, PCAT78, PCAT79, PCAT80, PCAT81, PCAT82, PCAT83,PCAT84, PCAT85, PCAT86, PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92,PCAT93, PCAT94, PCAT95, PCAT96, PCAT97, PCAT98, PCAT99, PCAT100,PCAT101, PCAT102, PCAT103, PCAT104, PCAT105, PCAT106, PCAT107, PCAT108,PCAT109, PCAT110, PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116,PCAT117, PCAT118, PCAT119, PCAT120, and PCAT121.

The system may further comprise an electronic memory for capturing andstoring an expression profile.

The system may further comprise a computer-processing device, optionallyconnected to a computer network.

The system may further comprise a software module executed by thecomputer-processing device to analyze an expression profile.

The system may further comprise a software module executed by thecomputer-processing device to compare the expression profile to astandard or control.

The system may further comprise a software module executed by thecomputer-processing device to determine the expression level of thetarget.

The system may further comprise a machine to isolate the target moleculeor the probe from the sample.

The system may further comprise a machine to sequence the targetmolecule or the probe.

The system may further comprise a machine to amplify the target moleculeor the probe.

The system may further comprise a label that specifically binds to thetarget molecule the probe, or a combination thereof.

The system may further comprise a software module executed by thecomputer-processing device to transmit an analysis of the expressionprofile to the subject or a medical professional treating the subject.

The system may further comprise a software module executed by thecomputer-processing device to transmit a diagnosis or prognosis to thesubject or a medical professional treating the subject.

Further disclosed herein are kits comprising (a) a probe set maycomprise a plurality of probes, wherein the plurality of probes maycomprise a sequence that hybridizes to at least a portion of one or moretarget molecules selected from the group may comprise PCAT, SChLAP-1,TU0011194, TU0019356, TU0024146, TU0009141, TU0062051, TU0021861, M41,ENST-75, and SEQ ID NOs: 1-9; and (b) a computer model or algorithm foranalyzing an expression level and/or expression profile of the targetmolecules in a sample.

The kit may further comprise a computer model or algorithm forcorrelating the expression level or expression profile with diseasestate or outcome.

The kit may further comprise a computer model or algorithm fordesignating a treatment modality for the subject.

The kit may further comprise a computer model or algorithm fornormalizing expression level or expression profile of the targetmolecules.

The kit may further comprise a computer model or algorithm may comprisea robust multichip average (RMA), probe logarithmic intensity errorestimation (PLIER), non-linear fit (NLFIT) quantile-based, nonlinearnormalization, or a combination thereof.

Methods for analyzing a cancer in a subject in need thereof may comprise(a) obtaining an expression profile from a sample obtained from thesubject, wherein the expression profile comprises one or more targetmolecules selected from PCAT, SChLAP-1, TU0011194, TU0019356, TU0024146,TU0009141, TU0062051, TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9; and(b) comparing the expression profile from the sample to an expressionprofile of a control or standard.

Disclosed herein may be methods, systems, compositions and kits fordiagnosing a cancer. Such methods for diagnosing cancer in a subject inneed thereof may comprise (a) obtaining an expression profile from asample obtained from the subject, wherein the expression profile maycomprise one or more target molecules selected from PCAT, SChLAP-1,TU0011194, TU0019356, TU0024146, TU0009141, TU0062051, TU0021861, M41,ENST-75, and SEQ ID NOs: 1-9; (b) comparing the expression profile fromthe sample to an expression profile of a control or standard; and (c)diagnosing a cancer in the subject if the expression profile of thesample (i) deviates from the control or standard from a healthy subjector population of healthy subjects, or (ii) matches the control orstandard from a subject or population of subjects who have or have hadthe cancer.

Disclosed herein may be methods, systems, compositions and kits forpredicting susceptibility to developing cancer. Such methods forpredicting whether a subject may be susceptible to developing a cancermay comprise (a) obtaining an expression profile from a sample obtainedfrom the subject, wherein the expression profile may comprise one ormore target molecules selected from PCAT, SChLAP-1, TU0011194,TU0019356, TU0024146, TU0009141, TU0062051, TU0021861, M41, ENST-75, andSEQ ID NOs: 1-9; (b) comparing the expression profile from the sample toan expression profile of a control or standard; and (c) predicting thesusceptibility of the subject for developing a cancer based on (i) thedeviation of the expression profile of the sample from a control orstandard derived from a healthy subject or population of healthysubjects, or (ii) the similarity of the expression profiles of thesample and a control or standard derived from a subject or population ofsubjects who have or have had the cancer.

Disclosed herein may be methods, systems, compositions and kits forpredicting response to a treatment regimen for cancer. Such methods forpredicting a subject's response to a treatment regimen for a cancer maycomprise: (a) obtaining an expression profile from a sample obtainedfrom the subject, wherein the expression profile may comprise one ormore target molecules selected from PCAT, SChLAP-1, TU0011194,TU0019356, TU0024146, TU0009141, TU0062051, TU0021861, M41, ENST-75, andSEQ ID NOs: 1-9; (b) comparing the expression profile from the sample toan expression profile of a control or standard; and (c) predicting thesubject's response to a treatment regimen based on (i) the deviation ofthe expression profile of the sample from a control or standard derivedfrom a healthy subject or population of healthy subjects, or (ii) thesimilarity of the expression profiles of the sample and a control orstandard derived from a subject or population of subjects who have orhave had the cancer.

Disclosed herein may be methods, systems, compositions and kits fortreating or determining a treatment regimen for cancer. Such methodstreating or determining a treatment regimen for cancer may comprise: (a)obtaining an expression profile from a sample obtained from the subject,wherein the expression profile may comprise one or more target moleculesselected from PCAT, SChLAP-1, TU0011194, TU0019356, TU0024146,TU0009141, TU0062051, TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9; (b)comparing the expression profile from the sample to an expressionprofile of a control or standard; and (c) treating or determining atreatment regimen for cancer based on (i) the deviation of theexpression profile of the sample from a control or standard derived froma healthy subject or population of healthy subjects, or (ii) thesimilarity of the expression profiles of the sample and a control orstandard derived from a subject or population of subjects who have orhave had the cancer.

The method may further comprise a software module executed by acomputer-processing device to compare the expression profiles.

The method may further comprise providing diagnostic or prognosticinformation to the subject about the cancer based on the comparison.

The method may further comprise diagnosing the subject with a cancer ifthe expression profile of the sample (a) deviates from the control orstandard from a healthy subject or population of healthy subjects, or(b) matches the control or standard from a subject or population ofsubjects who have or have had the cancer.

The method may further comprise predicting the susceptibility of thesubject for developing a cancer based on (a) the deviation of theexpression profile of the sample from a control or standard derived froma healthy subject or population of healthy subjects, or (b) thesimilarity of the expression profiles of the sample and a control orstandard derived from a subject or population of subjects who have orhave had the cancer.

The method may further comprise prescribing a treatment regimen based on(a) the deviation of the expression profile of the sample from a controlor standard derived from a healthy subject or population of healthysubjects, or (b) the similarity of the expression profiles of the sampleand a control or standard derived from a subject or population ofsubjects who have or have had the cancer.

The method may further comprise altering a treatment regimen prescribedor administered to the subject based on (a) the deviation of theexpression profile of the sample from a control or standard derived froma healthy subject or population of healthy subjects, or (b) thesimilarity of the expression profiles of the sample and a control orstandard derived from a subject or population of subjects who have orhave had the cancer.

The method may further comprise predicting the subject's response to atreatment regimen based on (a) the deviation of the expression profileof the sample from a control or standard derived from a healthy subjector population of healthy subjects, or (b) the similarity of theexpression profiles of the sample and a control or standard derived froma subject or population of subjects who have or have had the cancer.

The method may further comprise using a machine to isolate the one ormore target molecules, one or more probes, or one or more probehybridized target molecules from the sample.

The method may further comprise contacting the sample with a label thatspecifically binds to the target molecule, the probe, or a combinationthereof.

The method may further comprise contacting the sample with a label thatspecifically binds to one or more target molecules.

The method may further comprise amplifying at least a portion of thetarget molecule, the probe, or any combination thereof.

The method may further comprise sequencing at least a portion of thetarget molecule, the probe, or any combination thereof.

Further disclosed herein is a probe set for assessing a cancer status ofa subject may comprise a plurality of probes, wherein the probes in theprobe set may be capable of detecting an expression level of one or moretarget molecules selected from the group may comprise PCAT, SChLAP-1,TU0011194, TU0019356, TU0024146, TU0009141, TU0062051, TU0021861, M41,ENST-75, and SEQ ID NOs: 1-9, wherein The expression level of the one ormore target molecules may determine the cancer status of the subjectwith at least 40% accuracy.

The methods, systems, compositions and kits may comprise a plurality ofprobes. The plurality of probes may comprise a sequence that hybridizesto at least a portion of two or more target molecules selected from thegroup may comprise PCAT, SChLAP-1, TU0011194, TU0019356, TU0024146,TU0009141, TU0062051, TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9. Theplurality of probes may comprise a sequence that hybridizes to at leasta portion of three or more target molecules selected from the group maycomprise PCAT, SChLAP-1, TU0011194, TU0019356, TU0024146, TU0009141,TU0062051, TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9. The pluralityof probes may comprise a sequence that hybridizes to at least a portionof four or more target molecules selected from the group may comprisePCAT, SChLAP-1, TU0011194, TU0019356, TU0024146, TU0009141, TU0062051,TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9. The plurality of probesmay comprise a sequence that hybridizes to at least a portion of five ormore target molecules selected from the group may comprise PCAT,SChLAP-1, TU0011194, TU0019356, TU0024146, TU0009141, TU0062051,TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9. The plurality of probesmay comprise a sequence that hybridizes to at least a portion of ten ormore target molecules selected from the group may comprise PCAT,SChLAP-1, TU0011194, TU0019356, TU0024146, TU0009141, TU0062051,TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9.

The plurality of probes may comprise a sequence that hybridizes to atleast a portion of one or more target molecules selected from the groupmay comprise and SEQ ID NOs: 1-9. The plurality of probes may comprise asequence that hybridizes to at least a portion of one or more targetmolecules selected from the group may comprise PCAT1, PCAT14, PCAT43 andPCAT 109. The plurality of probes may comprise a sequence thathybridizes to at least a portion of one or more target molecules maycomprise SChLAP-1. The plurality of probes may comprise a sequence thathybridizes to at least a portion of one or more target moleculesselected from the group may comprise PCAT1, PCAT2, PCAT3, PCAT4, PCAT5,PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11, PCAT12, PCAT13, PCAT14,PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20, PCAT21, PCAT22, PCAT23,PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29, PCAT30, PCAT31, PCAT32,PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38, PCAT39, PCAT40, PCAT41,PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47, PCAT48, PCAT49, PCAT50,PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56, PCAT57, PCAT58, PCAT59,PCAT60, PCAT61, PCAT62, PCAT63, PCAT64, PCAT65, PCAT66, PCAT67, PCAT68,PCAT69, PCAT70, PCAT71, PCAT72, PCAT73, PCAT74, PCAT75, PCAT76, PCAT77,PCAT78, PCAT79, PCAT80, PCAT81, PCAT82, PCAT83, PCAT84, PCAT85, PCAT86,PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92, PCAT93, PCAT94, PCAT95,PCAT96, PCAT97, PCAT98, PCAT99, PCAT100, PCAT101, PCAT102, PCAT103,PCAT104, PCAT105, PCAT106, PCAT107, PCAT108, PCAT109, PCAT110, PCAT111,PCAT112, PCAT113, PCAT114, PCAT115, PCAT116, PCAT117, PCAT118, PCAT119,PCAT120, and PCAT121. The cancer may be a prostate cancer.

The plurality of probes may comprise a sequence that hybridizes to atleast a portion of one or more target molecules selected from the groupmay comprise M41 and ENST-75. The cancer may be a lung cancer.

The plurality of probes may comprise a sequence that hybridizes to atleast a portion of one or more target molecules selected from the groupmay comprise TU0011194, TU0019356 and TU0024146. The cancer may be abreast cancer.

The plurality of probes may comprise a sequence that hybridizes to atleast a portion of one or more target molecules selected from the groupmay comprise TU0011194, TU0019356 and TU0024146. The cancer may be apancreatic cancer.

The probes may be between about 15 nucleotides and about 500 nucleotidesin length. The probes may be between about 15 nucleotides and about 450nucleotides in length. The probes may be between about 15 nucleotidesand about 400 nucleotides in length. The probes may be between about 15nucleotides and about 350 nucleotides in length. The probes may bebetween about 15 nucleotides and about 300 nucleotides in length. Theprobes may be between about 15 nucleotides and about 250 nucleotides inlength. The probes may be between about 15 nucleotides and about 200nucleotides in length. The probes may be at least 15 nucleotides inlength. The probes may be at least 25 nucleotides in length.

The cancer may be selected from the group may comprise prostate, lung,breast, and pancreatic cancer.

Assessing the cancer status may comprise assessing cancer recurrencerisk. Assessing the cancer status may comprise determining a treatmentmodality. Assessing the cancer status may comprise determining theefficacy of treatment.

Obtaining an expression profile may comprise hybridizing one or moreprobes to the one or more target molecules to produce one or more probehybridized target molecules.

The deviation may be the expression level of one or more targets fromthe sample may be greater than the expression level of one or moretargets from a control or standard derived from a healthy subject orpopulation of healthy subjects. The deviation may be the expressionlevel of one or more targets from the sample may be at least about 30%greater than the expression level of one or more targets from a controlor standard derived from a healthy subject or population of healthysubjects. The deviation may be the expression level of one or moretargets from the sample may be less than the expression level of one ormore targets from a control or standard derived from a healthy subjector population of healthy subjects. The deviation may be the expressionlevel of one or more targets from the sample may be at least about 30%less than the expression level of one or more targets from a control orstandard derived from a healthy subject or population of healthysubjects.

The expression level of the one or more target molecules may determinethe cancer status of the subject with at least 50% accuracy. Theexpression level of the one or more target molecules may determine thecancer status of the subject with at least 60% accuracy. The expressionlevel of the one or more target molecules may determine the cancerstatus of the subject with at least 65% accuracy. The expression levelof the one or more target molecules may determine the cancer status ofthe subject with at least 70% accuracy. The expression level of the oneor more target molecules may determine the cancer status of the subjectwith at least 75% accuracy. The expression level of the one or moretarget molecules may determine the cancer status of the subject with atleast 80% accuracy.

The plurality of probes may determine the expression level of the one ormore target molecules with at least about 50% specificity. The pluralityof probes may determine the expression level of the one or more targetmolecules with at least about 60% specificity. The plurality of probesmay determine the expression level of the one or more target moleculeswith at least about 65% specificity. The plurality of probes maydetermine the expression level of the one or more target molecules withat least about 70% specificity. The plurality of probes may determinethe expression level of the one or more target molecules with at leastabout 75% specificity. The plurality of probes may determine theexpression level of the one or more target molecules with at least about80% specificity. The plurality of probes may determine the expressionlevel of the one or more target molecules with at least about 85%specificity.

The plurality of probes may determine the expression level of the one ormore target molecules with at least about 50% sensitivity. The pluralityof probes may determine the expression level of the one or more targetmolecules with at least about 60% sensitivity. The plurality of probesmay determine the expression level of the one or more target moleculeswith at least about 65% sensitivity. The plurality of probes maydetermine the expression level of the one or more target molecules withat least about 70% sensitivity. The plurality of probes may determinethe expression level of the one or more target molecules with at leastabout 75% sensitivity. The plurality of probes may determine theexpression level of the one or more target molecules with at least about80% sensitivity. The plurality of probes may determine the expressionlevel of the one or more target molecules with at least about 85%sensitivity.

Additional embodiments are described herein.

DESCRIPTION OF THE FIGURES

FIG. 1 shows that prostate cancer transcriptome sequencing revealsdysregulation of exemplary transcripts identified herein. a. A globaloverview of transcription in prostate cancer. b. A line graph showingthe cumulative fraction of genes that are expressed at a given RPKMlevel. c. Conservation analysis comparing unannotated transcripts toknown genes and intronic controls shows a low but detectable degree ofpurifying selection among intergenic and intronic unannotatedtranscripts. d-g. Intersection plots displaying the fraction ofunannotated transcripts enriched for H3K4me2 (d), H3K4me3 (e), Acetyl-H3(f) or RNA polymerase II (g) at their transcriptional start site (TSS)using ChIP-Seq and RNA-Seq data for the VCaP prostate cancer cancer cellline. h. A heatmap representing differentially expressed transcripts,including novel unannotated transcripts, in prostate cancer.

FIG. 2 shows that unannotated intergenic transcripts differentiateprostate cancer and benign prostate samples. a. A histogram plotting thegenomic distance between an unannotated ncRNA and the nearestprotein-coding gene. b. A Circos plot displaying the location ofannotated transcripts and unannotated transcripts on Chr15q. c. Aheatmap of differentially expressed or outlier unannotated intergenictranscripts clusters benign samples, localized tumors, and metastaticcancers by unsupervised clustering analyses. d. Cancer outlier profileanalysis (COPA) outlier analysis for the prostate cancer transcriptomereveals known outliers (SPINK1, ERG, and ETV1), as well as numerousunannotated transcripts.

FIG. 3 shows validation of tissue-specific prostate cancer-associatednon-coding RNAs. a-c. Quantitative real-time PCR was performed on apanel of prostate and non-prostate samples to measure expression levelsof three nominated non-coding RNAs (ncRNAs), PCAT-43, PCAT-109, andPCAT-14, upregulated in prostate cancer compared to normal prostatetissues. a. PCAT-43 is a 20 kb ncRNA located 40 kb upstream of PMEPA1 onchr20q13.31. b. PCAT-109, located in a large, 0.5 Mb gene desert regionon chr2q31.3 displays widespread transcription in prostate tissues,particularly metastases. c. PCAT-14, a genomic region on chr22q11.23encompassing a human endogenous retrovirus exhibits marked upregulationin prostate tumors but not metastases.

FIG. 4 shows that prostate cancer ncRNAs populate the Chr8q24 genedesert. a. A schematic of the chr8q24 region. b. Comprehensive analysisof the chr8q24 region by RNA-Seq and ChIP-Seq reveals numeroustranscripts supported by histone modifications, such as Acetyl-H3 andH3K4me3, demarcating active chromatin. c. RT-PCR and Sanger sequencingvalidation of the PCAT-1 exon-exon junction. d. The genomic location ofPCAT-1 determined by 5′ and 3′ RACE. Sequence analysis of PCAT-1 showsthat it is a viral long terminal repeat (LTR) promoter splicing to amarniner family transposase that has been bisected by an Alu repeat. e.qPCR on a panel of prostate and non-prostate samples showsprostate-specific expression and upregulation in prostate cancers andmetastases compared to benign prostate samples. f. Four matchedtumor/normal pairs included in the analysis in e. demonstrate somaticupregulation of PCAT-1 in matched cancer samples.

FIG. 5 shows that ncRNAs serve as urine biomarkers for prostate cancer.a-c. Three ncRNAs displaying biomarker status in prostate cancer tissueswere evaluated on a cohort of urine samples from 77 patients withprostate cancer and 31 controls with negative prostate biopsy resultsand absence of the TMPRSS2-ERG fusion transcript. PCA3 (a); PCAT-1 (b);and PCAT-14 (c). d. Scatter plots demonstrating distinct patient subsetsscoring positively for PCA3, PCAT-1, or PCAT-14 expression. e. A heatmapdisplaying patients positive and negative for several different prostatecancer biomarkers in urine sediment samples. f. A table displaying thestatistical significance of the ncRNA signature. g. A model fornon-coding RNA (ncRNA) activation in prostate cancer.

FIG. 6 shows Ab initio assembly of the prostate cancer transcriptome.(a) Reads were mapped with TopHat and assembled into library-specifictranscriptomes by Cufflinks. (b) Transcripts corresponding to processedpseudogenes were isolated, and the remaining transcripts werecategorized based on overlap with an aggregated set of known geneannotations.

FIG. 7 shows classification tree results for Chromosome 1. The recursiveregression and partitioning trees (rpart) machine learning algorithm wasused to predict expressed transcripts versus background signal.

FIG. 8 shows transcript assembly of known genes. ab initio transcriptassembly on prostate transcriptome sequencing data was used toreconstruct the known prostate transcriptome. a. SPINK1, a biomarker forprostate cancer. b. PRUNE2 with the PCA3 non-coding RNA within itsintronic regions. c. NFKB1. d. COL9A2.

FIG. 9 shows analysis of EST support for exemplary transcripts. ESTsfrom the UCSC database table “Human ESTs” were used to evaluate theamount of overlap between ESTs and novel transcripts. a. A line graphshowing the fraction of genes whose transcripts are supported by aparticular fraction of ESTs. b. A table displaying the number of ESTssupporting each class of transcripts

FIG. 10 shows analysis of coding potential of unannotated transcripts.DNA sequences for each transcript were extracted and searched for openreading frames (ORFs) using the txCdsPredict program from the UCSCsource tool set.

FIG. 11 shows repetitive content of novel transcripts. The percentage ofrepetitive sequences was assessed in all transcripts by calculating thepercentage of repeatmasked nucleotides in each sequence.

FIG. 12 shows distinct ChIP-Seq signatures for repeat-associated andnonrepeat novel ncRNAs. Unannotated transcripts were divided into twogroups, repeat-associated and non-repeat, and intersected with ChIP-Seqdata for Acetyl-H3 and H3K4me3, two histone modifications stronglyassociated with transcriptional start sites (TSS), in two prostatecancer cell lines. a. Acetyl-H3 in LNCaP cells. b. H3K4me3 in LNCaPcells. c. Acetyl-H3 in VCaP cells. d. H3K4me3 in VCaP cells.

FIG. 13 shows overlap of unannotated transcripts with ChIP-Seq data inVCaP cells. Previously published ChIP-Seq data for VCaP prostate cancercells were intersected with unannotated prostate cancer transcripts andannotated control genes. a. H3K4me1 b. H3K36me3.

FIG. 14 shows overlap of unannotated transcripts with ChIP-Seq data inLNCaP cells. ChIP-Seq data for LNCaP prostate cancer cells wereintersected with unannotated transcripts and annotated control genes.ncRNAs were divided into intergenic and intronic. a. H3K4me1 b. H3K4me2c. H3K4me3 d. Acetyl-H3 e. H3K36me3 f. RNA polymerase II.

FIG. 15 shows validation of a novel transcript on chromosome 15. a.Coverage maps showing the average expression levels (RPKM) across thebenign, localized tumor, and metastatic samples shows upregulation of anovel transcript downstream of TLE3. b. Several predicted isoforms ofthis transcript were nominated which retained common exons 1 and 2. c.The exon-exon boundary between exons 1 and 2, as well as an internalportion of exon 3, was validated by RT-PCR in prostate cell line models.d. Sanger sequencing of the RT-PCR product confirmed the junction ofexon 1 and exon 2.

FIG. 16 shows clustering of prostate cancer with outliers. Transcriptswith outlier profile scores in the top 10% were clustered usinghierarchical trees.

FIG. 17 shows validation of novel transcripts in prostate cell lines.11/14 unannotated transcripts selected for validation by RT-PCR and qPCRwere confirmed in cell line models. a. RT-PCR gels showing expectedbands for the 11 transcripts that validated. b. Representative qPCRresults using primers selected from a. The primers used in b areindicated by a red asterisk in a.

FIG. 18 shows that PCAT-14 is upregulated by androgen signaling. VCaPand LNCaP cells were treated 5 nM R1881 or vehicle (ethanol) control.

FIG. 19 shows that PCAT-14 is upregulated in matched tumor tissues. Fourmatched tumor-normal patient tissue samples were assayed for PCAT-14expression by qPCR.

FIG. 20 shows analysis of PCAT-14 transcript structure. a.Representative 5′RACE results using a 3′ primer confirms the presence ofthe sense transcript PCAT-14. Predicted novel transcripts are displayedabove the RACE results. b. DNA sequence analysis of PCAT-14 indicatesexpected splice donor sites, splice acceptor sites, and apolyadenylation site.

FIG. 21 shows analysis of PCAT-1 transcript structure. 5′ and 3′ RACEexperiments showed a ncRNA transcript containing two exons.

FIG. 22 shows that knockdown of PCAT-1 does not affect invasion orproliferation of VCaP cells. VCaP cells were transfected withcustom-made siRNAs targeting PCAT-1 or non-targeting controls. a.Knockdown efficiency for four siRNA oligos individually and pooled.b.-d. siRNAs 2-4 were tested for functional effect due to their higherefficiency of knockdown. b. A cell proliferation assay performed with aCoulter counter shows no significant difference in cell proliferationfollowing knockdown of PCAT-1. c. A WST-1 assay indicates no change inVCaP cell viability following PCAT-1 knockdown. d. A transmembraneinvasion assay shows no change in VCaP cell invasiveness followingPCAT-1 knockdown.

FIG. 23 shows transcription of two Alu elements in a CACNA1D intron. a.Coverage maps representing average expression in RPKM in benign samples,localized tumors, and prostate metastases. b. RPKM expression values forthe CACNA1D Alu transcript across the prostate transcriptome sequencingcohort. c. RT-PCR validation of the Alu transcript in cell line models.d. Sanger sequencing confirmation of RT-PCR fragments verifies thepresence of AluSp transcript sequence. e. Raw sequencing data of aportion of the AluSp sequence.

FIG. 24 shows transcription of numerous repeat elements at the SChLAP1locus. a. Coverage maps representing repeat elements transcribed at thechr2q31.3 locus. b. RPKM expression expression values for the LINE-1repeat region on chr2q31.3 across the prostate transcriptome sequencingcohort. c. RTPCR validation of the LINE-1 repetitive element in cellline models. A 402 bp fragment was amplified. d. Sanger sequencing ofthe PCR fragment confirms identity of the LINE-1 amplicon.

FIG. 25 shows a heatmap of repeats clusters prostate cancer samples.Unannotated transcripts that contained repeat elements were used tocluster prostate cancer samples in an unsupervised manner.

FIG. 26 shows that the SChLAP1 locus spans >500 kb. Visualization oftranscriptome sequencing data in the UCSC genome browser indicates thata large, almost 1 Mb section of chromosome 2 is highly activated incancer, contributing to many individual transcripts regulated in acoordinated fashion.

FIG. 27 shows that the SChLAP1 locus is associated with ETS positivetumors. a. Expression of the SChLAP1 locus was assayed by qPCR asdisplay in FIG. 3 b on a cohort of 14 benign prostate tissues, 47localized prostate tumors and 10 metastatic prostate cancers. b.Quantification of the SChLAP1 association with ETS status using thethreshold indicated by the blue dotted line in a.

FIG. 28 shows the sequence of PCAT-1 and PCAT-14.

FIG. 29 shows that PCAT-1 expression sensitizes prostate cancer cells totreatment with PARP-1 inhibitors. (a-d) treatment with the PARP 1inhibitor olaparib, (e-h) treatment with the PARP1 inhibitor ABT-888.Stable PCAT-1 knockdown in LNCAP prostate cells reduces sensitivity toolaparib (a) and ABT-888 (e). Stable overexpression in Du145 prostatecancer and RWPE benign prostate cells increases sensitivity to olaparib(b,c) and ABT-888 (f,g). Overexpression of PCAT-1 in MCF7 breast cancercells does not recapitulate this effect (d,h).

FIG. 30 shows that PCAT-1 expression sensitizes prostate cancer cells toradiation treatment. (a) Stable PCAT-1 knockdown in LNCAP prostate cellsreduces sensitivity to radiation. (b,c) Stable overexpression in Du145prostate cancer and RWPE benign prostate cells increases sensitivity toradiation. (d). Overexpression of PCAT-1 in MCF7 breast cancer cellsdoes not recapitulate this effect.

FIG. 31 shows that unannotated intergenic transcripts differentiateprostate cancer and benign samples. (a) The genomic location and exonstructure of SChLAP-1. SChLAP-1 is located on chromosome 2 in apreviously unannotated region. (b) The isoform structure of SChLAP-1.(c) Cell fractionation into nuclear and cytoplasmic fractionsdemonstrates that SChLAP-1 is predominantly nuclear in its localization.(d) Expression of SChLAP-1 in a cohort of prostate cancer and benigntissues indicates that SChLAP-1 is a prostate cancer outlier associatedwith cancers.

FIG. 32 shows that SChLAP-1 is required for prostate cancer cellinvasion and proliferation. (a) Prostate and non-prostate cancer celllines were treated with SChLAP-1 siRNAs. (b and c) As in (a), prostateand non-prostate cell lines were assayed for cell proliferationfollowing SChLAP-1 knockdown. (d) The three most abundant isoforms ofSChLAP-1 were cloned and overexpressed in RWPE benign immortalizedprostate cells at levels similar to LNCaP cancer cells. (e) RWPE cellsoverexpressing SChLAP-1 isoforms show an increased ability to invadethrough Matrigel in Boyden chamber assays.

FIG. 33 shows that deletion analysis of SChLAP-1 identifies a regionessential for its function. (a) RWPE cells overexpressing SChLAP-1deletion constructs or full-length isoform #1 were generated as shown inthe schematic of the constructs. (b) RWPE cells overexpressing SChLAP-1deletion constructs demonstrated an impaired ability to invade throughMatrigel, while the other deletion constructs showed no reduction intheir ability to induce RWPE cell invasion compared to the wild typeSChLAP-1.

FIG. 34 shows detection of prostate cancer RNAs in patient urinesamples. (a-e). (a) PCA3 (b) PCAT-14 (c) PCAT-1 (d) SChLAP-1 (e) PDLIM5

FIG. 35 shows multiplexing urine SChLAP-1 measurements with serum PSAimproves prostate cancer risk stratification.

FIG. 36 shows analysis of the lung cancer transcriptome. (a) 38 lungcell lines were analyzed by RNA-Seq and then lncRNA transcripts werereconstructed. (b) Expression levels of transcripts observed in lungcell lines. (c) An outlier analyses of 13 unannotated transcripts showsthe presence of novel lncRNAs in subtypes of lung cancer cell lines.

FIG. 37 shows discovery of M41 and ENST-75 in lung cancer. (a) Thegenomic location of M41, which resides in an intron of DSCAM. M41 ispoorly conserved across species. (b) qPCR of M41 demonstrates outlierexpression in 15-20% of lung adenocarcinomas as well as high expressionin breast cells. (c) The genomic location of ENST-75, which demonstrateshigh conservation across species. (d) qPCR of ENST-75 showsup-regulation in lung cancer but not breast or prostate cancers. Highexpression is observed in normal testis.

FIG. 38 shows lncRNAs are drivers and biomarkers in lung cancer. (a)Knockdown of ENST-75 in H1299 cells with independent siRNAsachieving >70% knockdown. (b) Knockdown of ENST-75 in H1299 cellsimpairs cell proliferation. Error bars represent s.e.m. (c) ENST-75expression in lung adenocarcinomas stratifies patient overall survival.(d) Serum detection levels of ENST-75 in normal and lung cancerpatients. (e) Average ENST-75 expression in lung cancer patient seracompared to normal patient sera. Error bars represent s.e.m.

FIG. 39 shows nomination of cancer-associated lncRNAs in breast andpancreatic cancer. (a-c) (a) TU0011194 (b) TU0019356 (c) TU0024146 (d-f)Three novel pancreatic cancer lncRNAs nominated from RNA-Seq data. Allshow outlier expression patterns in pancreatic cancer samples but notbenign samples. (d) TU0009141 (e) TU0062051 (f) TU0021861.

FIG. 40 shows discovery of SChLAP-1 as a prostate cancer lncRNA. (a)Cancer outlier profile analysis (COPA) for intergenic lncRNAs inprostate cancer nominates two transcripts, PCAT-109 and PCAT-114, asprominent outliers. (b) A comparison of lncRNA outliers nominated byCOPA, including their location, frequency in clinical samples, theirexpression in tissues and cell lines, and whether they occur inmetastatic prostate samples. (c) A representation of the SChLAP-1 geneand its annotations in current databases. SChLAP-1 may consist of up toseven exons on Chr2q31.3. (d) A schematic summarizing the observedSChLAP-1 isoforms. (e) qPCR for SChLAP-1 on a panel of benign prostate(n=33), localized prostate cancer (n=82), and metastatic prostate cancer(n=33) samples. (f) SChLAP-1 expression is predominantly nuclear.

FIG. 41 shows that SChLAP-1 coordinates prostate cancer cell invasion.(a) siRNA knockdown of SChLAP-1 in vitro. (b) Overexpression of SChLAP-1in RWPE cells. (c) Deletion analysis of SChLAP-1. (d) RNA structuralanalysis of SChLAP-1. (e) Tumor seeding with SChLAP-1 knockdown in vivo.(f) The number of gross metastatic sites observed by luciferase signalin 22Rv1 shSChLAP-1 cells or shNT controls. (g) Example luciferasebioluminescence images from 22Rv1 shNT, shSChLAP-1 #1, and shSChLAP-1 #2mice five weeks following intracardiac injection.

FIG. 42 shows that SChLAP-1 antagonizes SWI/SNF complex function. (a)Gene set enrichment analysis (GSEA) of LNCaP and 22Rv1 cells treatedwith SChLAP-1 siRNAs. (b) Heatmap results for SChLAP-1 or SWI/SNFknockdown in LNCaP and 22Rv1 cells. (c) GSEA analysis of SChLAP-1 andSWI/SNF knockdowns. (d) RNA immunoprecipitation (RIP) of SNF5 and ARdemonstrates SChLAP-1 binding to SNF5 in 22Rv1 and LNCaP cells. (e) RIPanalysis of SNF5 in RWPE cells overexpressing LacZ, SChLAP-1 isoform #1,SChLAP-1 isoform #2, or SChLAP-1 deletion construct 5.

FIG. 43 shows that SChLAP-1 expression characterizes aggressive prostatecancer. (a) Network representation of Oncomine concepts analysis ofgenes positively and negatively correlated with SChLAP-1 expressionlevels in localized prostate cancers profiled by RNA-Seq. (b) Heatmaprepresentation of comparisons between co-expression gene signatures andmolecular concepts. (c-e) Kaplan-Meier analyses of prostate canceroutcomes in the Mayo Clinic cohort. (c), clinical progression tosystemic disease (d), and prostate cancer-specific mortality (e). (f) Amodel of SChLAP-1 activity in prostate cancer.

FIG. 44 shows that chromosome 2 region contains prostatecancer-associated transcripts.

FIG. 45 shows the structure and sequence of SChLAP1.

FIG. 46 shows expression of SChLAP-1 across cancers.

DEFINITIONS

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below:

As used herein, the terms “detect”, “detecting” or “detection” maydescribe either the general act of discovering or discerning or thespecific observation of a composition. Detecting a composition maycomprise determining the presence or absence of a composition. Detectingmay comprise quantifying a composition. For example, detecting comprisesdetermining the expression level of a composition. The composition maycomprise a nucleic acid molecule. For example, the composition maycomprise at least a portion of the ncRNAs disclosed herein.Alternatively, or additionally, the composition may be a detectablylabeled composition.

As used herein, the term “subject” refers to any organisms that arescreened using the diagnostic methods described herein. Such organismspreferably include, but are not limited to, mammals (e.g., murines,simians, equines, bovines, porcines, canines, felines, and the like),and most preferably includes humans. Alternatively, the organism is anavian, amphibian, reptile or fish.

The term “diagnosed,” as used herein, refers to the recognition of adisease by its signs and symptoms, or genetic analysis, pathologicalanalysis, histological analysis, and the like.

A “subject suspected of having cancer” encompasses an individual who hasreceived an initial diagnosis (e.g., a CT scan showing a mass orincreased PSA level) but for whom the stage of cancer or presence orabsence of ncRNAs indicative of cancer is not known. The term furtherincludes people who once had cancer (e.g., an individual in remission).In some embodiments, “subjects” are control subjects that are suspectedof having cancer or diagnosed with cancer.

As used herein, the term “characterizing cancer in a subject” refers tothe identification of one or more properties of a cancer sample in asubject, including but not limited to, the presence of benign,pre-cancerous or cancerous tissue, the stage of the cancer, and thesubject's prognosis. Cancers may be characterized by the identificationof the expression of one or more cancer marker genes, including but notlimited to, the ncRNAs disclosed herein.

As used herein, the term “characterizing prostate tissue in a subject”refers to the identification of one or more properties of a prostatetissue sample (e.g., including but not limited to, the presence ofcancerous tissue, the presence or absence of ncRNAs, the presence ofpre-cancerous tissue that is likely to become cancerous, and thepresence of cancerous tissue that is likely to metastasize). In someembodiments, tissues are characterized by the identification of theexpression of one or more cancer marker genes, including but not limitedto, the cancer markers disclosed herein.

As used herein, the term “stage of cancer” refers to a qualitative orquantitative assessment of the level of advancement of a cancer.Criteria used to determine the stage of a cancer include, but are notlimited to, the size of the tumor and the extent of metastases (e.g.,localized or distant).

As used herein, the term “nucleic acid molecule” refers to any nucleicacid containing molecule, including but not limited to, DNA or RNA. Thenucleic acid molecule may comprise one or more nucleotides. The termencompasses sequences that include any of the known base analogs of DNAand RNA including, but not limited to, 4-acetylcytosine,8-hydroxy-N6-methyladenosine, aziridinylcytosine, pseudoisocytosine,5-(carboxyhydroxylmethyl) uracil, 5-fluorouracil, 5-bromouracil,5-carboxymethylaminomethyl-2-thiouracil,5-carboxymethyl-aminomethyluracil, dihydrouracil, inosine,N6-isopentenyladenine, 1-methyladenine, 1-methylpseudouracil,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-methyladenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarbonylmethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid methylester,uracil-5-oxyacetic acid, oxybutoxosine, pseudouracil, queosine,2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil,5-methyluracil, N-uracil-5-oxyacetic acid methylester,uracil-5-oxyacetic acid, pseudouracil, queosine, 2-thiocytosine, and2,6-diaminopurine.

The term “gene” refers to a nucleic acid (e.g., DNA) sequence thatcomprises coding sequences necessary for the production of apolypeptide, precursor, or RNA (e.g., rRNA, tRNA). The polypeptide canbe encoded by a full length coding sequence or by any portion of thecoding sequence so long as the desired activity or functional properties(e.g., enzymatic activity, ligand binding, signal transduction,immunogenicity, etc.) of the full-length or fragments are retained. Theterm also encompasses the coding region of a structural gene and thesequences located adjacent to the coding region on both the 5′ and 3′ends for a distance of about 1 kb or more on either end such that thegene corresponds to the length of the full-length mRNA. Sequenceslocated 5′ of the coding region and present on the mRNA are referred toas 5′ non-translated sequences. Sequences located 3′ or downstream ofthe coding region and present on the mRNA are referred to as 3′non-translated sequences. The term “gene” encompasses both cDNA andgenomic forms of a gene. A genomic form or clone of a gene contains thecoding region interrupted with non-coding sequences termed “introns” or“intervening regions” or “intervening sequences.” Introns are segmentsof a gene that are transcribed into nuclear RNA (hnRNA); introns maycontain regulatory elements such as enhancers. Introns are removed or“spliced out” from the nuclear or primary transcript; introns thereforeare absent in the messenger RNA (mRNA) transcript. The mRNA functionsduring translation to specify the sequence or order of amino acids in anascent polypeptide.

As used herein, the term “oligonucleotide,” refers to a short length ofsingle-stranded polynucleotide chain. Oligonucleotides are typicallyless than 200 residues long (e.g., between 15 and 100), however, as usedherein, the term is also intended to encompass longer polynucleotidechains. Oligonucleotides are often referred to by their length. Forexample a 24 residue oligonucleotide is referred to as a “24-mer”.Oligonucleotides can form secondary and tertiary structures byself-hybridizing or by hybridizing to other polynucleotides. Suchstructures can include, but are not limited to, duplexes, hairpins,cruciforms, bends, and triplexes.

As used herein, the terms “complementary” or “complementarity” are usedin reference to polynucleotides (i.e., a sequence of nucleotides)related by the base-pairing rules. For example, the sequence“5′-A-G-T-3′,” is complementary to the sequence “3′-T-C-A-5′.”Complementarity may be “partial,” in which only some of the nucleicacids' bases are matched according to the base pairing rules. Or, theremay be “complete” or “total” complementarity between the nucleic acids.The degree of complementarity between nucleic acid strands hassignificant effects on the efficiency and strength of hybridizationbetween nucleic acid strands. This is of particular importance inamplification reactions, as well as detection methods that depend uponbinding between nucleic acids.

The term “homology” refers to a degree of complementarity. There may bepartial homology or complete homology (i.e., identity). A partiallycomplementary sequence is a nucleic acid molecule that at leastpartially inhibits a completely complementary nucleic acid molecule fromhybridizing to a target nucleic acid is “substantially homologous.” Theinhibition of hybridization of the completely complementary sequence tothe target sequence may be examined using a hybridization assay(Southern or Northern blot, solution hybridization and the like) underconditions of low stringency. A substantially homologous sequence orprobe will compete for and inhibit the binding (i.e., the hybridization)of a completely homologous nucleic acid molecule to a target underconditions of low stringency. This is not to say that conditions of lowstringency are such that non-specific binding is permitted; lowstringency conditions require that the binding of two sequences to oneanother be a specific (i.e., selective) interaction. The absence ofnon-specific binding may be tested by the use of a second target that issubstantially non-complementary (e.g., less than about 30% identity); inthe absence of non-specific binding the probe will not hybridize to thesecond non-complementary target.

As used herein, the term “hybridization” is used in reference to thepairing of complementary nucleic acids. Hybridization and the strengthof hybridization (i.e., the strength of the association between thenucleic acids) is impacted by such factors as the degree ofcomplementary between the nucleic acids, stringency of the conditionsinvolved, the T_(m) of the formed hybrid, and the G:C ratio within thenucleic acids. A single molecule that contains pairing of complementarynucleic acids within its structure is said to be “self-hybridized.”

As used herein the term “stringency” is used in reference to theconditions of temperature, ionic strength, and the presence of othercompounds such as organic solvents, under which nucleic acidhybridizations are conducted. Under “low stringency conditions” anucleic acid sequence of interest will hybridize to its exactcomplement, sequences with single base mismatches, closely relatedsequences (e.g., sequences with 90% or greater homology), and sequenceshaving only partial homology (e.g., sequences with 50-90% homology).Under ‘medium stringency conditions,” a nucleic acid sequence ofinterest will hybridize only to its exact complement, sequences withsingle base mismatches, and closely relation sequences (e.g., 90% orgreater homology). Under “high stringency conditions,” a nucleic acidsequence of interest will hybridize only to its exact complement, and(depending on conditions such a temperature) sequences with single basemismatches. In other words, under conditions of high stringency thetemperature can be raised so as to exclude hybridization to sequenceswith single base mismatches.

The term “isolated” when used in relation to a nucleic acid, as in “anisolated oligonucleotide” or “isolated polynucleotide” refers to anucleic acid sequence that is identified and separated from at least onecomponent or contaminant with which it is ordinarily associated in itsnatural source. Isolated nucleic acid is such present in a form orsetting that is different from that in which it is found in nature. Incontrast, non-isolated nucleic acids as nucleic acids such as DNA andRNA found in the state they exist in nature. For example, a given DNAsequence (e.g., a gene) is found on the host cell chromosome inproximity to neighboring genes; RNA sequences, such as a specific mRNAsequence encoding a specific protein, are found in the cell as a mixturewith numerous other mRNAs that encode a multitude of proteins. However,isolated nucleic acid encoding a given protein includes, by way ofexample, such nucleic acid in cells ordinarily expressing the givenprotein where the nucleic acid is in a chromosomal location differentfrom that of natural cells, or is otherwise flanked by a differentnucleic acid sequence than that found in nature. The isolated nucleicacid, oligonucleotide, or polynucleotide may be present insingle-stranded or double-stranded form. When an isolated nucleic acid,oligonucleotide or polynucleotide is to be utilized to express aprotein, the oligonucleotide or polynucleotide will contain at a minimumthe sense or coding strand (i.e., the oligonucleotide or polynucleotidemay be single-stranded), but may contain both the sense and anti-sensestrands (i.e., the oligonucleotide or polynucleotide may bedouble-stranded).

As used herein, the term “purified” or “to purify” refers to the removalof components (e.g., contaminants) from a sample. For example,antibodies are purified by removal of contaminating non-immunoglobulinproteins; they are also purified by the removal of immunoglobulin thatdoes not bind to the target molecule. The removal of non-immunoglobulinproteins and/or the removal of immunoglobulins that do not bind to thetarget molecule results in an increase in the percent of target-reactiveimmunoglobulins in the sample. In another example, recombinantpolypeptides are expressed in bacterial host cells and the polypeptidesare purified by the removal of host cell proteins; the percent ofrecombinant polypeptides is thereby increased in the sample.

As used herein, the term “sample” is used in its broadest sense. In onesense, it is meant to include a specimen or culture obtained from anysource, as well as biological and environmental samples. Biologicalsamples may be obtained from animals (including humans) and encompassfluids, solids, tissues, and gases. Biological samples include bloodproducts, such as plasma, serum and the like. Such examples are nothowever to be construed as limiting the sample types applicable to thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compositions and methods for cancerdiagnosis, research and therapy, including but not limited to, cancermarkers. In particular, the present invention relates to ncRNAs asdiagnostic markers and clinical targets for cancer. ncRNAs may be usedas diagnostic markers and clinical targets for prostate, lung, breastand pancreatic cancer.

Experiments conducted during the development of embodiments of thepresent invention utilized RNA-Seq analyses of tissue samples and abinitio transcriptome assembly to predict the complete polyA+transcriptome of prostate cancer. 6,144 novel ncRNAs found in prostatecancer were identified, including 121 ncRNAs that associated withdisease progression (FIGS. 1, 2, 16 and 25). These data demonstrate theglobal utility of RNA-Seq in defining functionally-important elements ofthe genome.

The present invention is not limited to a particular mechanism. Indeed,an understanding of the mechanism is not necessary to practice thepresent invention. Nonetheless, although the biological role of theseRNAs, especially the differentially-expressed ones, is not yet known,these results indicate a model in which specific intergenic loci areactivated in prostate cancer, enabling the transcription of numerousdisease-specific and tissue-specific ncRNAs (FIG. 5 g). Clinically,these ncRNA signatures are suitable for urine-based assays to detect anddiagnose prostate cancer in a non-invasive manner (See e.g., Example 1).It is further contemplated that specific ncRNA signatures occuruniversally in all disease states and applying these methodologies toother diseases reveals clinically important biomarkers, particularly fordiseases that currently lack good protein biomarkers.

While traditional approaches have focused on the annotated referencegenome, data generated during the course of development of embodimentsof the present invention implicate large swaths of unannotated genomicloci in prostate cancer progression and prostate-specific expression.One example of this is the SChLAP1 locus, which represents a >500 kbstretch of coordinately regulated expression, and the chr8q24 locus,which contains a prostate specific region with the prostate cancerbiomarker PCAT-1. The fact that the SChLAP 1 locus is almost exclusivelyexpressed in prostate cancers harboring an ETS gene fusion furtherconfirms the capacity of ncRNAs to identify patient disease subtypes. Inaddition, these analyses reveal novel cancer-specific drivers oftumorigenesis. For example, the long ncRNA HOTAIR is known to directcancer-promoting roles for EZH2 in breast cancer (Gupta et al., Nature464 (7291), 1071 (2010)), while in the PC3 prostate cancer cell line asimilar role has been proposed for the ANRIL ncRNA (Yap et al., Mol Cell38 (5), 662 (2010)).

I. Diagnostic and Screening Methods

As described herein, embodiments of the present invention providediagnostic and screening methods that utilize the detection of one ormore ncRNAs. Exemplary ncRNAs include, but are not limited to, PCAT-1,PCAT-14, PCAT-43 and PCAT-109; SChLAP-1; and SEQ ID NOs: 1-9. Exemplary,non-limiting methods are described herein.

Any patient sample suspected of containing the ncRNAs may be testedaccording to methods of embodiments of the present invention. By way ofnon-limiting examples, the sample may be tissue (e.g., a biopsy sample,a prostate biopsy sample or a tissue sample obtained by prostatectomy),blood, urine, semen, prostatic secretions or a fraction thereof (e.g.,plasma, serum, urine supernatant, urine cell pellet, cells or prostatecells). A urine sample may be collected immediately following anattentive digital rectal examination (DRE), which causes prostate cellsfrom the prostate gland to shed into the urinary tract.

In some embodiments, the patient sample is subjected to preliminaryprocessing designed to isolate or enrich the sample for the ncRNAs orcells that contain the ncRNAs. A variety of techniques known to those ofordinary skill in the art may be used for this purpose, including butnot limited to: centrifugation; immunocapture; cell lysis; nucleic acidamplification; and, nucleic acid target capture (See, e.g., EP Pat. No.1 409 727, herein incorporated by reference in its entirety).

The ncRNAs may be detected along with other markers in a multiplex orpanel format. Markers may be selected for their predictive value aloneor in combination with the gene fusions. Exemplary prostate cancermarkers include, but are not limited to: AMACR/P504S (U.S. Pat. No.6,262,245); PCA3 (U.S. Pat. No. 7,008,765); PCGEM1 (U.S. Pat. No.6,828,429); prostein/P501S, P503S, P504S, P509S, P510S, prostase/P703P,P710P (U.S. Publication No. 20030185830); RAS/KRAS (Bos, Cancer Res.49:4682-89 (1989); Kranenburg, Biochimica et Biophysica Acta 1756:81-82(2005)); and, those disclosed in U.S. Pat. Nos. 5,854,206 and 6,034,218,7,229,774, each of which is herein incorporated by reference in itsentirety. Markers for other cancers, diseases, infections, and metabolicconditions are also contemplated for inclusion in a multiplex or panelformat.

In some embodiments, multiplex or array formats are utilized to detectmultiple markers in combination. For example, in some embodiments, thelevel of expression of one or more, 2 or more, 3 or more, 4 or more, 5or more, 10 or more, 15 or more, 20 or more, 25 or more, 30 or more, 35or more, 40 or more 45 or more, 50 or more, 60 or more, 70 or more, 80or more, 90 or more, 100 or more or all 121) non-coding RNAs (ncRNAs) isutilized in the research, screening, diagnostic and prognositiccompositions and methods described herein. The one or more ncRNAs may beselected from the group comprising SChLAP-1, PCAT1, PCAT2, PCAT3, PCAT4,PCAT5, PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11, PCAT12, PCAT13,PCAT14, PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20, PCAT21, PCAT22,PCAT23, PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29, PCAT30, PCAT31,PCAT32, PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38, PCAT39, PCAT40,PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47, PCAT48, PCAT49,PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56, PCAT57, PCAT58,PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64, PCAT65, PCAT66, PCAT67,PCAT68, PCAT69, PCAT70, PCAT71, PCAT72, PCAT73, PCAT74, PCAT75, PCAT76,PCAT77, PCAT78, PCAT79, PCAT80, PCAT81, PCAT82, PCAT83, PCAT84, PCAT85,PCAT86, PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92, PCAT93, PCAT94,PCAT95, PCAT96, PCAT97, PCAT98, PCAT99, PCAT100, PCAT101, PCAT102,PCAT103, PCAT104, PCAT105, PCAT106, PCAT107, PCAT108, PCAT109, PCAT110,PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116, PCAT117, PCAT118,PCAT119, PCAT120, and PCAT121.

i. DNA and RNA Detection

The ncRNAs of the present invention are detected using a variety ofnucleic acid techniques known to those of ordinary skill in the art,including but not limited to: nucleic acid sequencing; nucleic acidhybridization; and, nucleic acid amplification.

The methods, compositions and kits may comprise one or more ncRNAs. Themethods, compositions and kits may comprise 2 or more, 3 or more, 4 ormore, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more,15 or more, 20 or more, 25 or more, 30 or more, 40 or more, 45 or more,50 or more, 55 or more, 60 or more, 70 or more, 80 or more, 90 or more,100 or more, 110 or more, 120 or more, 130 or more, 140 or more, 150 ormore ncRNAs.

The one or more ncRNAs may be selected from the group comprising PCAT1,PCAT2, PCAT3, PCAT4, PCAT5, PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11,PCAT12, PCAT13, PCAT14, PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20,PCAT21, PCAT22, PCAT23, PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29,PCAT30, PCAT31, PCAT32, PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38,PCAT39, PCAT40, PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47,PCAT48, PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56,PCAT57, PCAT58, PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64, PCAT65,PCAT66, PCAT67, PCAT68, PCAT69, PCAT70, PCAT71, PCAT72, PCAT73, PCAT74,PCAT75, PCAT76, PCAT77, PCAT78, PCAT79, PCAT80, PCAT81, PCAT82, PCAT83,PCAT84, PCAT85, PCAT86, PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92,PCAT93, PCAT94, PCAT95, PCAT96, PCAT97, PCAT98, PCAT99, PCAT100,PCAT101, PCAT102, PCAT103, PCAT104, PCAT105, PCAT106, PCAT107, PCAT108,PCAT109, PCAT110, PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116,PCAT117, PCAT118, PCAT119, PCAT120, PCAT121, SChLAP-1, TU0011194,TU0019356, TU0024146, TU0009141, TU0062051, TU0021861, M41, ENST-75, andSEQ ID NOs: 1-9. The one or more ncRNAs of the present invention maycomprise one or more prostate cancer-associated ncRNA transcripts(PCATs). The one or more PCATs may be selected from the group comprisingPCAT1, PCAT2, PCAT3, PCAT4, PCAT5, PCAT6, PCAT7, PCAT8, PCAT9, PCAT10,PCAT11, PCAT12, PCAT13, PCAT14, PCAT15, PCAT16, PCAT17, PCAT18, PCAT19,PCAT20, PCAT21, PCAT22, PCAT23, PCAT24, PCAT25, PCAT26, PCAT27, PCAT28,PCAT29, PCAT30, PCAT31, PCAT32, PCAT33, PCAT34, PCAT35, PCAT36, PCAT37,PCAT38, PCAT39, PCAT40, PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46,PCAT47, PCAT48, PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55,PCAT56, PCAT57, PCAT58, PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64,PCAT65, PCAT66, PCAT67, PCAT68, PCAT69, PCAT70, PCAT71, PCAT72, PCAT73,PCAT74, PCAT75, PCAT76, PCAT77, PCAT78, PCAT79, PCAT80, PCAT81, PCAT82,PCAT83, PCAT84, PCAT85, PCAT86, PCAT87, PCAT88, PCAT89, PCAT90, PCAT91,PCAT92, PCAT93, PCAT94, PCAT95, PCAT96, PCAT97, PCAT98, PCAT99, PCAT100,PCAT101, PCAT102, PCAT103, PCAT104, PCAT105, PCAT106, PCAT107, PCAT108,PCAT109, PCAT110, PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116,PCAT117, PCAT118, PCAT119, PCAT120, and PCAT121. The one or more ncRNAsmay comprise PCAT1, PCAT14, PCAT43, PCAT 109, or a combination thereof.

Alternatively, or additionally, the ncRNAs of the present invention maycomprise SChLAP-1. The ncRNAs may comprise M41, ENST-75, or acombination thereof. The ncRNAs may comprise TU0011194, TU0019356,TU0024146, or a combination thereof. The ncRNAs may comprise TU0009141,TU0062051, TU0021861 or a combination thereof. The ncRNAs may compriseany one of SEQ ID NOs: 1-9 or a combination thereof.

1. Sequencing

Illustrative non-limiting examples of nucleic acid sequencing techniquesinclude, but are not limited to, chain terminator (Sanger) sequencingand dye terminator sequencing. Those of ordinary skill in the art willrecognize that because RNA is less stable in the cell and more prone tonuclease attack experimentally RNA is usually reverse transcribed to DNAbefore sequencing.

Chain terminator sequencing uses sequence-specific termination of a DNAsynthesis reaction using modified nucleotide substrates. Extension isinitiated at a specific site on the template DNA by using a shortradioactive, or other labeled, oligonucleotide primer complementary tothe template at that region. The oligonucleotide primer is extendedusing a DNA polymerase, standard four deoxynucleotide bases, and a lowconcentration of one chain terminating nucleotide, most commonly adi-deoxynucleotide. This reaction is repeated in four separate tubeswith each of the bases taking turns as the di-deoxynucleotide. Limitedincorporation of the chain terminating nucleotide by the DNA polymeraseresults in a series of related DNA fragments that are terminated only atpositions where that particular di-deoxynucleotide is used. For eachreaction tube, the fragments are size-separated by electrophoresis in aslab polyacrylamide gel or a capillary tube filled with a viscouspolymer. The sequence is determined by reading which lane produces avisualized mark from the labeled primer as you scan from the top of thegel to the bottom.

Dye terminator sequencing alternatively labels the terminators. Completesequencing can be performed in a single reaction by labeling each of thedi-deoxynucleotide chain-terminators with a separate fluorescent dye,which fluoresces at a different wavelength.

A variety of nucleic acid sequencing methods are contemplated for use inthe methods of the present disclosure including, for example, chainterminator (Sanger) sequencing, dye terminator sequencing, andhigh-throughput sequencing methods. Many of these sequencing methods arewell known in the art. See, e.g., Sanger et al., Proc. Natl. Acad. Sci.USA 74:5463-5467 (1997); Maxam et al., Proc. Natl. Acad. Sci. USA74:560-564 (1977); Drmanac, et al., Nat. Biotechnol. 16:54-58 (1998);Kato, Int. J. Clin. Exp. Med. 2:193-202 (2009); Ronaghi et al., Anal.Biochem. 242:84-89 (1996); Margulies et al., Nature 437:376-380 (2005);Ruparel et al., Proc. Natl. Acad. Sci. USA 102:5932-5937 (2005), andHarris et al., Science 320:106-109 (2008); Levene et al., Science299:682-686 (2003); Korlach et al., Proc. Natl. Acad. Sci. USA105:1176-1181 (2008); Branton et al., Nat. Biotechnol. 26(10):1146-53(2008); Eid et al., Science 323:133-138 (2009); each of which is hereinincorporated by reference in its entirety.

The methods disclosed herein can comprise transcriptome sequencing(e.g., RNA-Seq). Sequencing can comprise platforms such as the IlluminaGenome Analyzer platform, ABI Solid Sequencing or Life Science's 454Sequencing. Alternatively, sequencing comprises Helicos' Direct RNASequencing (DRS™) technology. The sequencing reactions may comprisecapillary sequencing, next generation sequencing, Sanger sequencing,sequencing by synthesis, single molecule nanopore sequencing, sequencingby ligation, sequencing by hybridization, sequencing by nanopore currentrestriction, or a combination thereof. Sequencing by synthesis maycomprise reversible terminator sequencing, processive single moleculesequencing, sequential nucleotide flow sequencing, or a combinationthereof. Sequential nucleotide flow sequencing may comprisepyrosequencing, pH-mediated sequencing, semiconductor sequencing or acombination thereof. Conducting one or more sequencing reactionscomprises whole genome sequencing or exome sequencing.

2. Hybridization

Illustrative non-limiting examples of nucleic acid hybridizationtechniques include, but are not limited to, in situ hybridization (ISH),microarray, and Southern or Northern blot. In situ hybridization (ISH)is a type of hybridization that uses a labeled complementary DNA or RNAstrand as a probe to localize a specific DNA or RNA sequence in aportion or section of tissue (in situ), or, if the tissue is smallenough, the entire tissue (whole mount ISH). DNA ISH can be used todetermine the structure of chromosomes. RNA ISH is used to measure andlocalize mRNAs and other transcripts (e.g., ncRNAs) within tissuesections or whole mounts. Sample cells and tissues are usually treatedto fix the target transcripts in place and to increase access of theprobe. The probe hybridizes to the target sequence at elevatedtemperature, and then the excess probe is washed away. The probe thatwas labeled with either radio-, fluorescent- or antigen-labeled bases islocalized and quantitated in the tissue using either autoradiography,fluorescence microscopy or immunohistochemistry, respectively. ISH canalso use two or more probes, labeled with radioactivity or the othernon-radioactive labels, to simultaneously detect two or moretranscripts.

In some embodiments, ncRNAs are detected using fluorescence in situhybridization (FISH). In some embodiments, FISH assays utilize bacterialartificial chromosomes (BACs). These have been used extensively in thehuman genome sequencing project (see Nature 409: 953-958 (2001)) andclones containing specific BACs are available through distributors thatcan be located through many sources, e.g., NCBI. Each BAC clone from thehuman genome has been given a reference name that unambiguouslyidentifies it. These names can be used to find a corresponding GenBanksequence and to order copies of the clone from a distributor.

The present invention further provides a method of performing a FISHassay on the patient sample. The methods disclosed herein may compriseperforming a FISH assay on one or more cells, tissues, organs, or fluidssurrounding such cells, tissues and organs. In some instances, themethods disclosed herein further comprise performing a FISH assay onhuman prostate cells, human prostate tissue or on the fluid surroundingsaid human prostate cells or human prostate tissue. Alternatively, oradditionally, the methods disclosed herein comprise performing a FISHassay on breast cells, lung cells, pancreatic cells, liver cells, breasttissue, lung tissue, pancreatic tissue, liver tissue, or on the fluidsurrounding the cells or tissues. Specific protocols are well known inthe art and can be readily adapted for the present invention. Guidanceregarding methodology may be obtained from many references including: Insitu Hybridization: Medical Applications (eds. G. R. Coulton and J. deBelleroche), Kluwer Academic Publishers, Boston (1992); In situHybridization: In Neurobiology; Advances in Methodology (eds. J. H.Eberwine, K. L. Valentino, and J. D. Barchas), Oxford University PressInc., England (1994); In situ Hybridization: A Practical Approach (ed.D. G. Wilkinson), Oxford University Press Inc., England (1992)); Kuo, etal., Am. J. Hum. Genet. 49:112-119 (1991); Klinger, et al., Am. J. Hum.Genet. 51:55-65 (1992); and Ward, et al., Am. J. Hum. Genet. 52:854-865(1993)). There are also kits that are commercially available and thatprovide protocols for performing FISH assays (available from e.g.,Oncor, Inc., Gaithersburg, Md.). Patents providing guidance onmethodology include U.S. Pat. Nos. 5,225,326; 5,545,524; 6,121,489 and6,573,043. All of these references are hereby incorporated by referencein their entirety and may be used along with similar references in theart and with the information provided in the Examples section herein toestablish procedural steps convenient for a particular laboratory.

The one or more ncRNAs may be detected by conducting one or morehybridization reactions. The one or more hybridization reactions maycomprise one or more hybridization arrays, hybridization reactions,hybridization chain reactions, isothermal hybridization reactions,nucleic acid hybridization reactions, or a combination thereof. The oneor more hybridization arrays may comprise hybridization arraygenotyping, hybridization array proportional sensing, DNA hybridizationarrays, macroarrays, microarrays, high-density oligonucleotide arrays,genomic hybridization arrays, comparative hybridization arrays, or acombination thereof.

3. Microarrays

Different kinds of biological assays are called microarrays including,but not limited to: DNA microarrays (e.g., cDNA microarrays andoligonucleotide microarrays); protein microarrays; tissue microarrays;transfection or cell microarrays; chemical compound microarrays; and,antibody microarrays. A DNA microarray, commonly known as gene chip, DNAchip, or biochip, is a collection of microscopic DNA spots attached to asolid surface (e.g., glass, plastic or silicon chip) forming an arrayfor the purpose of expression profiling or monitoring expression levelsfor thousands of genes simultaneously. The affixed DNA segments areknown as probes, thousands of which can be used in a single DNAmicroarray. Microarrays can be used to identify disease genes ortranscripts (e.g., ncRNAs) by comparing gene expression in disease andnormal cells. Microarrays can be fabricated using a variety oftechnologies, including but not limiting: printing with fine-pointedpins onto glass slides; photolithography using pre-made masks;photolithography using dynamic micromirror devices; ink-jet printing;or, electrochemistry on microelectrode arrays.

3. Amplification

The methods disclosed herein may comprise conducting one or moreamplification reactions. Nucleic acids (e.g., ncRNAs) may be amplifiedprior to or simultaneous with detection. Conducting one or moreamplification reactions may comprise one or more PCR-basedamplifications, non-PCR based amplifications, or a combination thereof.Illustrative non-limiting examples of nucleic acid amplificationtechniques include, but are not limited to, polymerase chain reaction(PCR), reverse transcription polymerase chain reaction (RT-PCR), nestedPCR, linear amplification, multiple displacement amplification (MDA),real-time SDA, rolling circle amplification, circle-to-circleamplification transcription-mediated amplification (TMA), ligase chainreaction (LCR), strand displacement amplification (SDA), and nucleicacid sequence based amplification (NASBA). Those of ordinary skill inthe art will recognize that certain amplification techniques (e.g., PCR)require that RNA be reversed transcribed to DNA prior to amplification(e.g., RT-PCR), whereas other amplification techniques directly amplifyRNA (e.g., TMA and NASBA).

The polymerase chain reaction (U.S. Pat. Nos. 4,683,195, 4,683,202,4,800,159 and 4,965,188, each of which is herein incorporated byreference in its entirety), commonly referred to as PCR, uses multiplecycles of denaturation, annealing of primer pairs to opposite strands,and primer extension to exponentially increase copy numbers of a targetnucleic acid sequence. In a variation called RT-PCR, reversetranscriptase (RT) is used to make a complementary DNA (cDNA) from mRNA,and the cDNA is then amplified by PCR to produce multiple copies of DNA.For other various permutations of PCR see, e.g., U.S. Pat. Nos.4,683,195, 4,683,202 and 4,800,159; Mullis et al., Meth. Enzymol. 155:335 (1987); and, Murakawa et al., DNA 7: 287 (1988), each of which isherein incorporated by reference in its entirety.

Transcription mediated amplification (U.S. Pat. Nos. 5,480,784 and5,399,491, each of which is herein incorporated by reference in itsentirety), commonly referred to as TMA, synthesizes multiple copies of atarget nucleic acid sequence autocatalytically under conditions ofsubstantially constant temperature, ionic strength, and pH in whichmultiple RNA copies of the target sequence autocatalytically generateadditional copies. See, e.g., U.S. Pat. Nos. 5,399,491 and 5,824,518,each of which is herein incorporated by reference in its entirety. In avariation described in U.S. Publ. No. 20060046265 (herein incorporatedby reference in its entirety), TMA optionally incorporates the use ofblocking moieties, terminating moieties, and other modifying moieties toimprove TMA process sensitivity and accuracy.

The ligase chain reaction (Weiss, R., Science 254: 1292 (1991), hereinincorporated by reference in its entirety), commonly referred to as LCR,uses two sets of complementary DNA oligonucleotides that hybridize toadjacent regions of the target nucleic acid. The DNA oligonucleotidesare covalently linked by a DNA ligase in repeated cycles of thermaldenaturation, hybridization and ligation to produce a detectabledouble-stranded ligated oligonucleotide product.

Strand displacement amplification (Walker, G. et al., Proc. Natl. Acad.Sci. USA 89: 392-396 (1992); U.S. Pat. Nos. 5,270,184 and 5,455,166,each of which is herein incorporated by reference in its entirety),commonly referred to as SDA, uses cycles of annealing pairs of primersequences to opposite strands of a target sequence, primer extension inthe presence of a dNTPαS to produce a duplex hemiphosphorothioatedprimer extension product, endonuclease-mediated nicking of ahemimodified restriction endonuclease recognition site, andpolymerase-mediated primer extension from the 3′ end of the nick todisplace an existing strand and produce a strand for the next round ofprimer annealing, nicking and strand displacement, resulting ingeometric amplification of product. Thermophilic SDA (tSDA) usesthermophilic endonucleases and polymerases at higher temperatures inessentially the same method (EP Pat. No. 0 684 315).

Other amplification methods include, for example: nucleic acid sequencebased amplification (U.S. Pat. No. 5,130,238, herein incorporated byreference in its entirety), commonly referred to as NASBA; one that usesan RNA replicase to amplify the probe molecule itself (Lizardi et al.,BioTechnol. 6: 1197 (1988), herein incorporated by reference in itsentirety), commonly referred to as Qβ replicase; a transcription basedamplification method (Kwoh et al., Proc. Natl. Acad. Sci. USA 86:1173(1989)); and, self-sustained sequence replication (Guatelli et al.,Proc. Natl. Acad. Sci. USA 87: 1874 (1990), each of which is hereinincorporated by reference in its entirety). For further discussion ofknown amplification methods see Persing, David H., “In Vitro NucleicAcid Amplification Techniques” in Diagnostic Medical Microbiology:Principles and Applications (Persing et al., Eds.), pp. 51-87 (AmericanSociety for Microbiology, Washington, D.C. (1993)).

4. Detection Methods

Non-amplified or amplified nucleic acids can be detected by anyconventional means. For example, the ncRNAs can be detected byhybridization with a detectably labeled probe and measurement of theresulting hybrids. In another example, the ncRNAs can be detected bysequencing. Illustrative non-limiting examples of detection methods aredescribed herein.

One illustrative detection method, the Hybridization Protection Assay(HPA) involves hybridizing a chemiluminescent oligonucleotide probe(e.g., an acridinium ester-labeled (AE) probe) to the target sequence,selectively hydrolyzing the chemiluminescent label present onunhybridized probe, and measuring the chemiluminescence produced fromthe remaining probe in a luminometer. See, e.g., U.S. Pat. No. 5,283,174and Norman C. Nelson et al., Nonisotopic Probing, Blotting, andSequencing, ch. 17 (Larry J. Kricka ed., 2d ed. 1995, each of which isherein incorporated by reference in its entirety).

Another illustrative detection method provides for quantitativeevaluation of the amplification process in real-time. Evaluation of anamplification process in “real-time” involves determining the amount ofamplicon in the reaction mixture either continuously or periodicallyduring the amplification reaction, and using the determined values tocalculate the amount of target sequence initially present in the sample.A variety of methods for determining the amount of initial targetsequence present in a sample based on real-time amplification are wellknown in the art. These include methods disclosed in U.S. Pat. Nos.6,303,305 and 6,541,205, each of which is herein incorporated byreference in its entirety. Another method for determining the quantityof target sequence initially present in a sample, but which is not basedon a real-time amplification, is disclosed in U.S. Pat. No. 5,710,029,herein incorporated by reference in its entirety.

Amplification products may be detected in real-time through the use ofvarious self-hybridizing probes, most of which have a stem-loopstructure. Such self-hybridizing probes are labeled so that they emitdifferently detectable signals, depending on whether the probes are in aself-hybridized state or an altered state through hybridization to atarget sequence. By way of non-limiting example, “molecular torches” area type of self-hybridizing probe that includes distinct regions ofself-complementarity (referred to as “the target binding domain” and“the target closing domain”) which are connected by a joining region(e.g., non-nucleotide linker) and which hybridize to each other underpredetermined hybridization assay conditions. In a preferred embodiment,molecular torches contain single-stranded base regions in the targetbinding domain that are from 1 to about 20 bases in length and areaccessible for hybridization to a target sequence present in anamplification reaction under strand displacement conditions. Understrand displacement conditions, hybridization of the two complementaryregions, which may be fully or partially complementary, of the moleculartorch is favored, except in the presence of the target sequence, whichwill bind to the single-stranded region present in the target bindingdomain and displace all or a portion of the target closing domain. Thetarget binding domain and the target closing domain of a molecular torchinclude a detectable label or a pair of interacting labels (e.g.,luminescent/quencher) positioned so that a different signal is producedwhen the molecular torch is self-hybridized than when the moleculartorch is hybridized to the target sequence, thereby permitting detectionof probe:target duplexes in a test sample in the presence ofunhybridized molecular torches. Molecular torches and a variety of typesof interacting label pairs are disclosed in U.S. Pat. No. 6,534,274,herein incorporated by reference in its entirety.

Another example of a detection probe having self-complementarity is a“molecular beacon.” Molecular beacons include nucleic acid moleculeshaving a target complementary sequence, an affinity pair (or nucleicacid arms) holding the probe in a closed conformation in the absence ofa target sequence present in an amplification reaction, and a label pairthat interacts when the probe is in a closed conformation. Hybridizationof the target sequence and the target complementary sequence separatesthe members of the affinity pair, thereby shifting the probe to an openconformation. The shift to the open conformation is detectable due toreduced interaction of the label pair, which may be, for example, afluorophore and a quencher (e.g., DABCYL and EDANS). Molecular beaconsare disclosed in U.S. Pat. Nos. 5,925,517 and 6,150,097, hereinincorporated by reference in its entirety.

Other self-hybridizing probes are well known to those of ordinary skillin the art. By way of non-limiting example, probe binding pairs havinginteracting labels, such as those disclosed in U.S. Pat. No. 5,928,862(herein incorporated by reference in its entirety) might be adapted foruse in the present invention. Probe systems used to detect singlenucleotide polymorphisms (SNPs) might also be utilized in the presentinvention. Additional detection systems include “molecular switches,” asdisclosed in U.S. Publ. No. 20050042638, herein incorporated byreference in its entirety. Other probes, such as those comprisingintercalating dyes and/or fluorochromes, are also useful for detectionof amplification products in the present invention. See, e.g., U.S. Pat.No. 5,814,447 (herein incorporated by reference in its entirety).Additional detection methods may include microarrays and electrophoresis(e.g., gel electrophoresis). Detection methods can be quantitative orsemi-quantitative. Detection methods may also comprise the use of one ormore labels (e.g., radioisotopes, fluorophores, chemiluminophores,enzymes, colloidal particles, and fluorescent microparticles, as well asantigens, antibodies, haptens, avidin/streptavidin, biotin, haptens, orenzyme cofactors/substrates, enzymes).

Southern and Northern blotting is used to detect specific DNA or RNAsequences, respectively. DNA or RNA extracted from a sample isfragmented, electrophoretically separated on a matrix gel, andtransferred to a membrane filter. The filter bound DNA or RNA is subjectto hybridization with a labeled probe complementary to the sequence ofinterest. Hybridized probe bound to the filter is detected. A variant ofthe procedure is the reverse Northern blot, in which the substratenucleic acid that is affixed to the membrane is a collection of isolatedDNA fragments and the probe is RNA extracted from a tissue and labeled.

ii. In vivo Imaging

ncRNAs may also be detected using in vivo imaging techniques, includingbut not limited to: radionuclide imaging; positron emission tomography(PET); computerized axial tomography, X-ray or magnetic resonanceimaging method, fluorescence detection, and chemiluminescent detection.In some embodiments, in vivo imaging techniques are used to visualizethe presence of or expression of cancer markers in an animal (e.g., ahuman or non-human mammal). For example, in some embodiments, cancermarker mRNA or protein is labeled using a labeled antibody specific forthe cancer marker. A specifically bound and labeled antibody can bedetected in an individual using an in vivo imaging method, including,but not limited to, radionuclide imaging, positron emission tomography,computerized axial tomography, X-ray or magnetic resonance imagingmethod, fluorescence detection, and chemiluminescent detection. Methodsfor generating antibodies to the cancer markers of the present inventionare described below.

The in vivo imaging methods of embodiments of the present invention areuseful in the identification of cancers that express ncRNAs (e.g.,prostate cancer). In vivo imaging is used to visualize the presence orlevel of expression of a ncRNA. Such techniques allow for diagnosiswithout the use of an unpleasant biopsy. The in vivo imaging methods ofembodiments of the present invention can further be used to detectmetastatic cancers in other parts of the body.

In some embodiments, reagents (e.g., antibodies) specific for the cancermarkers of the present invention are fluorescently labeled. The labeledantibodies are introduced into a subject (e.g., orally or parenterally).Fluorescently labeled antibodies are detected using any suitable method(e.g., using the apparatus described in U.S. Pat. No. 6,198,107, hereinincorporated by reference).

In other embodiments, antibodies are radioactively labeled. The use ofantibodies for in vivo diagnosis is well known in the art. Sumerdon etal., (Nucl. Med. Biol 17:247-254 [1990] have described an optimizedantibody-chelator for the radioimmunoscintographic imaging of tumorsusing Indium-111 as the label. Griffin et al., (J Clin One 9:631-640[1991]) have described the use of this agent in detecting tumors inpatients suspected of having recurrent colorectal cancer. The use ofsimilar agents with paramagnetic ions as labels for magnetic resonanceimaging is known in the art (Lauffer, Magnetic Resonance in Medicine22:339-342 [1991]). The label used will depend on the imaging modalitychosen. Radioactive labels such as Indium-111, Technetium-99m, orIodine-131 can be used for planar scans or single photon emissioncomputed tomography (SPECT). Positron emitting labels such asFluorine-19 can also be used for positron emission tomography (PET). ForMRI, paramagnetic ions such as Gadolinium (III) or Manganese (II) can beused.

Radioactive metals with half-lives ranging from 1 hour to 3.5 days areavailable for conjugation to antibodies, such as scandium-47 (3.5 days)gallium-67 (2.8 days), gallium-68 (68 minutes), technetiium-99m (6hours), and indium-111 (3.2 days), of which gallium-67, technetium-99m,and indium-111 are preferable for gamma camera imaging, gallium-68 ispreferable for positron emission tomography.

A useful method of labeling antibodies with such radiometals is by meansof a bifunctional chelating agent, such as diethylenetriaminepentaaceticacid (DTPA), as described, for example, by Khaw et al. (Science 209:295[1980]) for In-111 and Tc-99m, and by Scheinberg et al. (Science215:1511 [1982]). Other chelating agents may also be used, but the1-(p-carboxymethoxybenzyl)EDTA and the carboxycarbonic anhydride of DTPAare advantageous because their use permits conjugation without affectingthe antibody's immunoreactivity substantially.

Another method for coupling DPTA to proteins is by use of the cyclicanhydride of DTPA, as described by Hnatowich et al. (Int. J. Appl.Radiat. Isot. 33:327 [1982]) for labeling of albumin with In-111, butwhich can be adapted for labeling of antibodies. A suitable method oflabeling antibodies with Tc-99m which does not use chelation with DPTAis the pretinning method of Crockford et al., (U.S. Pat. No. 4,323,546,herein incorporated by reference).

A method of labeling immunoglobulins with Tc-99m is that described byWong et al. (Int. J. Appl. Radiat. Isot., 29:251 [1978]) for plasmaprotein, and recently applied successfully by Wong et al. (J. Nucl.Med., 23:229 [1981]) for labeling antibodies.

In the case of the radiometals conjugated to the specific antibody, itis likewise desirable to introduce as high a proportion of theradiolabel as possible into the antibody molecule without destroying itsimmunospecificity. A further improvement may be achieved by effectingradiolabeling in the presence of the ncRNA, to insure that the antigenbinding site on the antibody will be protected. The antigen is separatedafter labeling.

In still further embodiments, in vivo biophotonic imaging (Xenogen,Almeda, Calif.) is utilized for in vivo imaging. This real-time in vivoimaging utilizes luciferase. The luciferase gene is incorporated intocells, microorganisms, and animals (e.g., as a fusion protein with acancer marker of the present invention). When active, it leads to areaction that emits light. A CCD camera and software is used to capturethe image and analyze it.

iii. Data Analysis

In some embodiments, a computer-based analysis program is used totranslate the raw data generated by the detection assay (e.g., thepresence, absence, or amount of a given marker or markers) into data ofpredictive value for a clinician. The clinician can access thepredictive data using any suitable means. Thus, in some preferredembodiments, the present invention provides the further benefit that theclinician, who is not likely to be trained in genetics or molecularbiology, need not understand the raw data. The data is presenteddirectly to the clinician in its most useful form. The clinician is thenable to immediately utilize the information in order to optimize thecare of the subject.

The present invention contemplates any method capable of receiving,processing, and transmitting the information to and from laboratoriesconducting the assays, information providers, medical personnel, andsubjects. For example, in some embodiments of the present invention, asample (e.g., a biopsy or a serum or urine sample) is obtained from asubject and submitted to a profiling service (e.g., clinical lab at amedical facility, genomic profiling business, etc.), located in any partof the world (e.g., in a country different than the country where thesubject resides or where the information is ultimately used) to generateraw data. Where the sample comprises a tissue or other biologicalsample, the subject may visit a medical center to have the sampleobtained and sent to the profiling center, or subjects may collect thesample themselves (e.g., a urine sample) and directly send it to aprofiling center. Where the sample comprises previously determinedbiological information, the information may be directly sent to theprofiling service by the subject (e.g., an information card containingthe information may be scanned by a computer and the data transmitted toa computer of the profiling center using an electronic communicationsystems). Once received by the profiling service, the sample isprocessed and a profile is produced (i.e., expression data), specificfor the diagnostic or prognostic information desired for the subject.

The profile data is then prepared in a format suitable forinterpretation by one or more medical personnel (e.g., a treatingclinician, physician assistant, nurse, or pharmacist). For example,rather than providing raw expression data, the prepared format mayrepresent a diagnosis or risk assessment (e.g., presence or absence of ancRNA) for the subject, along with recommendations for particulartreatment options. The data may be displayed to the medical personnel byany suitable method. For example, in some embodiments, the profilingservice generates a report that can be printed for the medical personnel(e.g., at the point of care) or displayed to the medical personnel on acomputer monitor.

In some embodiments, the information is first analyzed at the point ofcare or at a regional facility. The raw data is then sent to a centralprocessing facility for further analysis and/or to convert the raw datato information useful for medical personnel or patient. The centralprocessing facility provides the advantage of privacy (all data isstored in a central facility with uniform security protocols), speed,and uniformity of data analysis. The central processing facility canthen control the fate of the data following treatment of the subject.For example, using an electronic communication system, the centralfacility can provide data to the medical personnel, the subject, orresearchers.

In some embodiments, the subject is able to directly access the datausing the electronic communication system. The subject may chose furtherintervention or counseling based on the results.

In some embodiments, the data is used for research use. For example, thedata may be used to further optimize the inclusion or elimination ofmarkers as useful indicators of a particular condition or stage ofdisease or as a companion diagnostic to determine a treatment course ofaction.

iv. Compositions & Kits

Compositions for use in the diagnostic methods described herein include,but are not limited to, probes, amplification oligonucleotides, and thelike.

The probe and antibody compositions of the present invention may also beprovided in the form of an array.

The compositions and kits may comprise 1 or more, 2 or more, 3 or more,4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 ormore, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 20 ormore, 25 or more, 30 or more, 35 or more, 40 or more, 45 or more, 50 ormore, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 110or more, 120 or more probes.

The probes may hybridize to 1 or more, 2 or more, 3 or more, 4 or more,5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 ormore, 12 or more, 13 or more, 14 or more, 15 or more, 20 or more, 25 ormore, 30 or more, 35 or more, 40 or more, 45 or more, 50 or more, 60 ormore, 70 or more, 80 or more, 90 or more, 100 or more, 110 or more, 120or more target molecules. The target molecules may be a ncRNA, RNA, DNA,cDNA, mRNA, a portion or fragment thereof or a combination thereof. Insome instances, at least a portion of the target molecules are ncRNAs.The probes may hybridize to 1 or more, 2 or more, 3 or more, 4 or more,5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 ormore, 12 or more, 13 or more, 14 or more, 15 or more, 20 or more, 25 ormore, 30 or more, 35 or more, 40 or more, 45 or more, 50 or more, 60 ormore, 70 or more, 80 or more, 90 or more, 100 or more, 110 or more, 120or more ncRNAs disclosed herein.

Typically, the probes comprise a target specific sequence. The targetspecific sequence may be complementary to at least a portion of thetarget molecule. The target specific sequence may be at least about 50%or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% ormore, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more,98% or more, or 100% complementary to at least a portion of the targetmolecule.

The target specific sequence may be at least about 5 or more, 6 or more,7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19or more, 20 or more nucleotides in length. In some instances, the targetspecific sequence is between about 8 to about 20 nucleotides, 10 toabout 18 nucleotides, or 12 to about 16 nucleotides in length.

The compositions and kits may comprise a plurality of probes, whereinthe two or more probes of the plurality of probes comprise identicaltarget specific sequences. The compositions and kits may comprise aplurality of probes, wherein the two or more probes of the plurality ofprobes comprise different target specific sequences.

The probes may further comprise a unique sequence. The unique sequenceis noncomplementary to the ncRNA. The unique sequence may comprise alabel, barcode, or unique identifier. The unique sequence may comprise arandom sequence, nonrandom sequence, or a combination thereof. Theunique sequence may be at least about 5 or more, 6 or more, 7 or more, 8or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20or more, 22 or more, 24 or more, 26 or more, 28 or more, 30 or morenucleotides in length. In some instances, the unique sequence is betweenabout 8 to about 20 nucleotides, 10 to about 18 nucleotides, or 12 toabout 16 nucleotides in length.

The unique sequence may allow differentiation of two or more targetmolecules. The two or more target molecules may have identicalsequences. Thus, the unique sequence may allow quantification of atarget molecule. Alternatively, the two or more target molecules mayhave different sequences. Thus, the unique sequence may allow detectionof the target molecules. The compositions and kits may comprise aplurality of probes for quantifying one or more target molecules. Thecompositions and kits may comprise a plurality of probes for detectingone or more target molecules.

The unique sequence may allow differentiation of two or more samples.The compositions and kits may comprise 1 or more, 2 or more, 3 or more,4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 ormore, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 20 ormore, 25 or more, 30 or more probe sets for differentiating two or moresamples from one or more subjects. The two or more samples may be fromtwo or more different subjects. For example, the compositions and kitscomprise a first set of probes comprising a first unique sequence thatis specific for a first subject and a second set of probes comprising asecond unique sequence that is specific for a second subject. Thecompositions and kits may further comprise one or more sets of probeswith one or more unique sequences to differentiate one or moreadditional subjects.

The compositions and kits may comprise 2 or more probe sets fordifferentiating from 2 or more, 3 or more, 4 or more, 5 or more, 6 ormore, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 ormore, 13 or more, 14 or more, 15 or more, 20 or more, 25 or more, 30 ormore samples from 1 or more subjects.

The compositions and kits may comprise 2 or more probe sets fordifferentiating 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 ormore, 13 or more, 14 or more, 15 or more, 20 or more, 25 or more, 30 ormore samples from one or more cells, tissues, organs, bodily fluid, or acombination thereof.

The compositions and kits may comprise 2 or more probe sets fordifferentiating samples from 1 or more, 2 or more, 3 or more, 4 or more,5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 ormore, 12 or more, 13 or more, 14 or more, 15 or more, 20 or more, 25 ormore, 30 or more subjects.

Alternatively, or additionally, the two or more samples may be from twoor more different timepoints from the same subject or differentsubjects. For example, the compositions and kits comprise a first set ofprobes comprising a first unique sequence that is specific for a firstsubject and a second set of probes comprising a second unique sequencethat is specific for a second subject. The compositions and kits maycomprise 2 or more probe sets for differentiating samples from 1 ormore, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more,8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14or more, 15 or more, 20 or more, 25 or more, 30 or more timepoints. Thetimepoints may be every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or more hours. The timepoints maybe every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24 or more days. The timepoints may be every 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24 or more weeks. The timepoints may be every 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or moremonths. The timepoints may be every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or more years. Thetimepoints may be before diagnosis, after diagnosis, before treatment,during treatment, after treatment, before metastasis, after metastatis,before remission, during remission, or a combination thereof.

The compositions and kits may comprise a first probe comprising a firsttarget-specific sequence and a first unique sequence and a second probecomprising a second target-specific sequence and a second uniquesequence, wherein the first target specific sequence and the secondtarget specific sequence are identical and the first unique sequence andthe second unique sequence are different. The compositions and kits maycomprise a first probe comprising a first target-specific sequence and afirst unique sequence and a second probe comprising a secondtarget-specific sequence and a second unique sequence, wherein the firsttarget specific sequence and the second target specific sequence aredifferent and the first unique sequence and the second unique sequenceare different. The compositions and kits may comprise a first probecomprising a first target-specific sequence and a first unique sequenceand a second probe comprising a second target-specific sequence and asecond unique sequence, wherein the first target specific sequence andthe second target specific sequence are identical and the first uniquesequence and the second unique sequence are identical. The compositionsand kits may comprise a first probe comprising a first target-specificsequence and a first unique sequence and a second probe comprising asecond target-specific sequence and a second unique sequence, whereinthe first target specific sequence and the second target specificsequence are different and the first unique sequence and the secondunique sequence are identical.

The probes may further comprise a universal sequence. The universalsequence may comprise a primer binding site. The universal sequence mayenable detection of the target sequence. The universal sequence mayenable amplification of the target sequence. The universal sequence mayenable transcription or reverse transcription of the target sequence.The universal sequence may enable sequencing of the target sequence.

The probe and antibody compositions of the present invention may also beprovided on a solid support. The solid support may comprise one or morebeads, plates, solid surfaces, wells, chips, or a combination thereof.The beads may be magnetic, antibody coated, protein A crosslinked,protein G crosslinked, streptavidin coated, oligonucleotide conjugated,silica coated, or a combination thereof. Examples of beads include, butare not limited to, Ampure beads, AMPure XP beads, streptavidin beads,agarose beads, magnetic beads, Dynabeads®, MACS® microbeads, antibodyconjugated beads (e.g., anti-immunoglobulin microbead), protein Aconjugated beads, protein G conjugated beads, protein A/G conjugatedbeads, protein L conjugated beads, oligo-dT conjugated beads, silicabeads, silica-like beads, anti-biotin microbead, anti-fluorochromemicrobead, and BcMag™ Carboxy-Terminated Magnetic Beads.

The compositions and kits may comprise primers and primer pairs capableof amplifying target molecules, or fragments or subsequences orcomplements thereof. The nucleotide sequences of the target moleculesmay be provided in computer-readable media for in silico applicationsand as a basis for the design of appropriate primers for amplificationof one or more target molecules.

Primers based on the nucleotide sequences of target molecules can bedesigned for use in amplification of the target molecules. For use inamplification reactions such as PCR, a pair of primers can be used. Theexact composition of the primer sequences is not critical to theinvention, but for most applications the primers may hybridize tospecific sequences of the target molecules or the universal sequence ofthe probe under stringent conditions, particularly under conditions ofhigh stringency, as known in the art. The pairs of primers are usuallychosen so as to generate an amplification product of at least about 15or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70or more, 80 or more, 90 or more, 100 or more, 125 or more, 150 or more,175 or more, 200 or more, 250 or more, 300 or more, 350 or more, 400 ormore, 450 or more, 500 or more, 600 or more, 700 or more, 800 or more,900 or more, or 1000 or more nucleotides. Algorithms for the selectionof primer sequences are generally known, and are available in commercialsoftware packages. These primers may be used in standard quantitative orqualitative PCR-based assays to assess transcript expression levels oftarget molecules. Alternatively, these primers may be used incombination with probes, such as molecular beacons in amplificationsusing real-time PCR.

One skilled in the art also appreciates that the nucleotide sequence ofthe entire length of the primer does not need to be derived from thetarget sequence. Thus, for example, the primer may comprise nucleotidesequences at the 5′ and/or 3′ termini that are not derived from thetarget molecule. Nucleotide sequences which are not derived from thenucleotide sequence of the target molecule may provide additionalfunctionality to the primer. For example, they may provide a restrictionenzyme recognition sequence or a “tag” that facilitates detection,isolation, purification or immobilization onto a solid support.Alternatively, the additional nucleotides may provide aself-complementary sequence that allows the primer to adopt a hairpinconfiguration. Such configurations may be necessary for certain primers,for example, molecular beacon and Scorpion primers, which can be used insolution hybridization techniques.

The probes or primers can incorporate moieties useful in detection,isolation, purification, or immobilization, if desired. Such moietiesare well-known in the art (see, for example, Ausubel et al., (1997 &updates) Current Protocols in Molecular Biology, Wiley & Sons, New York)and are chosen such that the ability of the probe to hybridize with itstarget molecule is not affected.

Examples of suitable moieties are detectable labels, such asradioisotopes, fluorophores, chemiluminophores, enzymes, colloidalparticles, and fluorescent microparticles, as well as antigens,antibodies, haptens, avidin/streptavidin, biotin, haptens, enzymecofactors/substrates, enzymes, and the like.

A label can optionally be attached to or incorporated into a probe orprimer to allow detection and/or quantitation of a target polynucleotiderepresenting the target molecule of interest. The target polynucleotidemay be the expressed target molecule RNA itself, a cDNA copy thereof, oran amplification product derived therefrom, and may be the positive ornegative strand, so long as it can be specifically detected in the assaybeing used. Similarly, an antibody may be labeled.

In certain multiplex formats, labels used for detecting different targetmolecules may be distinguishable. The label can be attached directly(e.g., via covalent linkage) or indirectly, e.g., via a bridgingmolecule or series of molecules (e.g., a molecule or complex that canbind to an assay component, or via members of a binding pair that can beincorporated into assay components, e.g. biotin-avidin or streptavidin).Many labels are commercially available in activated forms which canreadily be used for such conjugation (for example through amineacylation), or labels may be attached through known or determinableconjugation schemes, many of which are known in the art.

Labels useful in the invention described herein include any substancewhich can be detected when bound to or incorporated into the targetmolecule. Any effective detection method can be used, including optical,spectroscopic, electrical, piezoelectrical, magnetic, Raman scattering,surface plasmon resonance, colorimetric, calorimetric, etc. A label istypically selected from a chromophore, a lumiphore, a fluorophore, onemember of a quenching system, a chromogen, a hapten, an antigen, amagnetic particle, a material exhibiting nonlinear optics, asemiconductor nanocrystal, a metal nanoparticle, an enzyme, an antibodyor binding portion or equivalent thereof, an aptamer, and one member ofa binding pair, and combinations thereof. Quenching schemes may be used,wherein a quencher and a fluorophore as members of a quenching pair maybe used on a probe, such that a change in optical parameters occurs uponbinding to the target introduce or quench the signal from thefluorophore. One example of such a system is a molecular beacon.Suitable quencher/fluorophore systems are known in the art. The labelmay be bound through a variety of intermediate linkages. For example, atarget polynucleotide may comprise a biotin-binding species, and anoptically detectable label may be conjugated to biotin and then bound tothe labeled target polynucleotide. Similarly, a polynucleotide sensormay comprise an immunological species such as an antibody or fragment,and a secondary antibody containing an optically detectable label may beadded.

Chromophores useful in the methods described herein include anysubstance which can absorb energy and emit light. For multiplexedassays, a plurality of different signaling chromophores can be used withdetectably different emission spectra. The chromophore can be alumophore or a fluorophore. Typical fluorophores include fluorescentdyes, semiconductor nanocrystals, lanthanide chelates,polynucleotide-specific dyes and green fluorescent protein.

Coding schemes may optionally be used, comprising encoded particlesand/or encoded tags associated with different polynucleotides of theinvention. A variety of different coding schemes are known in the art,including fluorophores, including SCNCs, deposited metals, and RF tags.

Polynucleotides from the described target molecules may be employed asprobes for detecting target molecules expression, for ligationamplification schemes, or may be used as primers for amplificationschemes of all or a portion of a target molecules. When amplified,either strand produced by amplification may be provided in purifiedand/or isolated form.

In some instances, the compositions and kits comprise a biomarkerlibrary. The biomarker library may comprise 1 or more, 2 or more, 3 ormore, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more,10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more,20 or more, 25 or more, 30 or more, 35 or more, 40 or more, 45 or more,50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more,110 or more, 120 or more target molecules. The target molecules may be ancRNA, RNA, DNA, cDNA, mRNA, a portion or fragment thereof or acombination thereof. In some instances, at least a portion of the targetmolecules are ncRNAs. The biomarker library may comprise 1 or more, 2 ormore, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more,9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more,15 or more, 20 or more, 25 or more, 30 or more, 35 or more, 40 or more,45 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more,100 or more, 110 or more, 120 or more ncRNAs disclosed herein. Thebiomarker library may comprise one or more PCATs, SChLAP-1, M41,ENST-75, TU0011194, TU0019356, TU0024146, TU0009141, TU0062051,TU0021861, M41, ENST-75, any one of SEQ ID NOs 1-9, or a combinationthereof.

In some embodiments, is a kit for analyzing a cancer comprising (a) aprobe set comprising a plurality of probes comprising target specificsequences complementary to one or more target molecules, wherein the oneor more target molecules comprise one or more ncRNAs; and (b) a computermodel or algorithm for analyzing an expression level and/or expressionprofile of the one or more target molecules in a sample. The targetmolecules may comprise one or more PCATs, SChLAP-1, M41, ENST-75,TU0011194, TU0019356, TU0024146, TU0009141, TU0062051, TU0021861, anyone of SEQ ID NOs 1-9, or a combination thereof.

In some embodiments, is a kit for analyzing a cancer comprising (a) aprobe set comprising a plurality of probes comprising target specificsequences complementary to one or more target molecules of a biomarkerlibrary; and (b) a computer model or algorithm for analyzing anexpression level and/or expression profile of the one or more targetmolecules in a sample. Control samples and/or nucleic acids mayoptionally be provided in the kit. Control samples may include tissueand/or nucleic acids obtained from or representative of tumor samplesfrom a healthy subject, as well as tissue and/or nucleic acids obtainedfrom or representative of tumor samples from subjects diagnosed with acancer.

Instructions for using the kit to perform one or more methods of theinvention can be provided, and can be provided in any fixed medium. Theinstructions may be located inside or outside a container or housing,and/or may be printed on the interior or exterior of any surfacethereof. A kit may be in multiplex form for concurrently detectingand/or quantitating one or more different target polynucleotidesrepresenting the expressed target molecules.

v. Devices

Devices useful for performing methods of the invention are alsoprovided. The devices can comprise means for characterizing theexpression level of a target molecule of the invention, for examplecomponents for performing one or more methods of nucleic acidextraction, amplification, and/or detection. Such components may includeone or more of an amplification chamber (for example a thermal cycler),a plate reader, a spectrophotometer, capillary electrophoresisapparatus, a chip reader, and or robotic sample handling components.These components ultimately can obtain data that reflects the expressionlevel of the target molecules used in the assay being employed.

The devices may include an excitation and/or a detection means. Anyinstrument that provides a wavelength that can excite a species ofinterest and is shorter than the emission wavelength(s) to be detectedcan be used for excitation. Commercially available devices can providesuitable excitation wavelengths as well as suitable detection component.

Exemplary excitation sources include a broadband UV light source such asa deuterium lamp with an appropriate filter, the output of a white lightsource such as a xenon lamp or a deuterium lamp after passing through amonochromator to extract out the desired wavelength(s), a continuouswave (cw) gas laser, a solid state diode laser, or any of the pulsedlasers. Emitted light can be detected through any suitable device ortechnique; many suitable approaches are known in the art. For example, afluorimeter or spectrophotometer may be used to detect whether the testsample emits light of a wavelength characteristic of a label used in anassay.

The devices typically comprise a means for identifying a given sample,and of linking the results obtained to that sample. Such means caninclude manual labels, barcodes, and other indicators which can belinked to a sample vessel, and/or may optionally be included in thesample itself, for example where an encoded particle is added to thesample. The results may be linked to the sample, for example in acomputer memory that contains a sample designation and a record ofexpression levels obtained from the sample. Linkage of the results tothe sample can also include a linkage to a particular sample receptaclein the device, which is also linked to the sample identity.

The devices also comprise a means for correlating the expression levelsof the target molecules being studied with a prognosis of diseaseoutcome. Such means may comprise one or more of a variety of correlativetechniques, including lookup tables, algorithms, multivariate models,and linear or nonlinear combinations of expression models or algorithms.The expression levels may be converted to one or more likelihood scores,reflecting a likelihood that the patient providing the sample mayexhibit a particular disease outcome. The models and/or algorithms canbe provided in machine readable format and can optionally furtherdesignate a treatment modality for a patient or class of patients.

The device also comprises output means for outputting the diseasestatus, prognosis and/or a treatment modality. Such output means cantake any form which transmits the results to a patient and/or ahealthcare provider, and may include a monitor, a printed format, orboth. The device may use a computer system for performing one or more ofthe steps provided.

The methods disclosed herein may also comprise the transmission ofdata/information. For example, data/information derived from thedetection and/or quantification of the target may be transmitted toanother device and/or instrument. In some instances, the informationobtained from an algorithm may also be transmitted to another deviceand/or instrument. Transmission of the data/information may comprise thetransfer of data/information from a first source to a second source. Thefirst and second sources may be in the same approximate location (e.g.,within the same room, building, block, campus). Alternatively, first andsecond sources may be in multiple locations (e.g., multiple cities,states, countries, continents, etc).

Transmission of the data/information may comprise digital transmissionor analog transmission. Digital transmission may comprise the physicaltransfer of data (a digital bit stream) over a point-to-point orpoint-to-multipoint communication channel. Examples of such channels arecopper wires, optical fibres, wireless communication channels, andstorage media. The data may be represented as an electromagnetic signal,such as an electrical voltage, radiowave, microwave, or infrared signal.

Analog transmission may comprise the transfer of a continuously varyinganalog signal. The messages can either be represented by a sequence ofpulses by means of a line code (baseband transmission), or by a limitedset of continuously varying wave forms (passband transmission), using adigital modulation method. The passband modulation and correspondingdemodulation (also known as detection) can be carried out by modemequipment. According to the most common definition of digital signal,both baseband and passband signals representing bit-streams areconsidered as digital transmission, while an alternative definition onlyconsiders the baseband signal as digital, and passband transmission ofdigital data as a form of digital-to-analog conversion.

vii. Samples

Samples for use with the compositions and kits and in the methods of thepresent invention comprise nucleic acids suitable for providing RNAexpression information. In principle, the biological sample from whichthe expressed RNA is obtained and analyzed for target moleculeexpression can be any material suspected of comprising cancer tissue orcells. The sample can be a biological sample used directly in a methodof the invention. Alternatively, the sample can be a sample preparedfrom a biological sample.

In one embodiment, the sample or portion of the sample comprising orsuspected of comprising cancer tissue or cells can be any source ofbiological material, including cells, tissue, secretions, or fluid,including bodily fluids. Non-limiting examples of the source of thesample include an aspirate, a needle biopsy, a cytology pellet, a bulktissue preparation or a section thereof obtained for example by surgeryor autopsy, lymph fluid, blood, plasma, serum, tumors, and organs.Alternatively, or additionally, the source of the sample can be urine,bile, excrement, sweat, tears, vaginal fluids, spinal fluid, and stool.In some instances, the sources of the sample are secretions. In someinstances, the secretions are exosomes.

The samples may be archival samples, having a known and documentedmedical outcome, or may be samples from current patients whose ultimatemedical outcome is not yet known.

In some embodiments, the sample may be dissected prior to molecularanalysis. The sample may be prepared via macrodissection of a bulk tumorspecimen or portion thereof, or may be treated via microdissection, forexample via Laser Capture Microdissection (LCM).

The sample may initially be provided in a variety of states, as freshtissue, fresh frozen tissue, fine needle aspirates, and may be fixed orunfixed. Frequently, medical laboratories routinely prepare medicalsamples in a fixed state, which facilitates tissue storage. A variety offixatives can be used to fix tissue to stabilize the morphology ofcells, and may be used alone or in combination with other agents.Exemplary fixatives include crosslinking agents, alcohols, acetone,Bouin's solution, Zenker solution, Hely solution, osmic acid solutionand Carnoy solution.

Crosslinking fixatives can comprise any agent suitable for forming twoor more covalent bonds, for example, an aldehyde. Sources of aldehydestypically used for fixation include formaldehyde, paraformaldehyde,glutaraldehyde or formalin. Preferably, the crosslinking agent comprisesformaldehyde, which may be included in its native form or in the form ofparaformaldehyde or formalin. One of skill in the art would appreciatethat for samples in which crosslinking fixatives have been used specialpreparatory steps may be necessary including for example heating stepsand proteinase-k digestion.

One or more alcohols may be used to fix tissue, alone or in combinationwith other fixatives. Exemplary alcohols used for fixation includemethanol, ethanol and isopropanol.

Formalin fixation is frequently used in medical laboratories. Formalincomprises both an alcohol, typically methanol, and formaldehyde, both ofwhich can act to fix a biological sample.

Whether fixed or unfixed, the biological sample may optionally beembedded in an embedding medium. Exemplary embedding media used inhistology including paraffin, Tissue-Tek® V.I.P.™, Paramat, ParamatExtra, Paraplast, Paraplast X-tra, Paraplast Plus, Peel Away ParaffinEmbedding Wax, Polyester Wax, Carbowax Polyethylene Glycol, Polyfin™,Tissue Freezing Medium TFMFM, Cryo-Gef™, and OCT Compound (ElectronMicroscopy Sciences, Hatfield, Pa.). Prior to molecular analysis, theembedding material may be removed via any suitable techniques, as knownin the art. For example, where the sample is embedded in wax, theembedding material may be removed by extraction with organic solvent(s),for example xylenes. Kits are commercially available for removingembedding media from tissues. Samples or sections thereof may besubjected to further processing steps as needed, for example serialhydration or dehydration steps.

In some embodiments, the sample is a fixed, wax-embedded biologicalsample. Frequently, samples from medical laboratories are provided asfixed, wax-embedded samples, most commonly as formalin-fixed, paraffinembedded (FFPE) tissues.

Whatever the source of the biological sample, the target polynucleotidethat is ultimately assayed can be prepared synthetically (in the case ofcontrol sequences), but typically is purified from the biological sourceand subjected to one or more preparative steps. The RNA may be purifiedto remove or diminish one or more undesired components from thebiological sample or to concentrate it. Conversely, where the RNA is tooconcentrated for the particular assay, it may be diluted.

II. Drug Screening Applications

In some embodiments, the present invention provides drug screeningassays (e.g., to screen for anticancer drugs). The screening methods ofthe present invention utilize ncRNAs. For example, in some embodiments,the present invention provides methods of screening for compounds thatalter the expression or activity of ncRNAs. The compounds may increasethe expression or activity of the ncRNAs. The compounds may decrease theexpression or activity of the ncRNAs. The compounds or agents mayinterfere with transcription, by interacting, for example, with thepromoter region. The compounds or agents may interfere with mRNA (e.g.,by RNA interference, antisense technologies, etc.). The compounds oragents may interfere with pathways that are upstream or downstream ofthe biological activity of ncRNAs. In some embodiments, candidatecompounds are antisense or interfering RNA agents (e.g.,oligonucleotides) directed against ncRNAs. In other embodiments,candidate compounds are antibodies or small molecules that specificallybind to a ncRNA regulator. Alternatively, or additionally, the candidatecompounds are expression products that inhibit the biological functionof the ncRNAs.

In one screening method, candidate compounds are evaluated for theirability to alter ncRNAs expression by contacting a compound with a cellexpressing a ncRNA and then assaying for the effect of the candidatecompounds on expression. In some embodiments, the effect of candidatecompounds on expression of ncRNAs is assayed for by detecting the levelncRNA expressed by the cell. mRNA expression can be detected by anysuitable method.

III. Diagnosis, Prognosis, and Monitoring

The methods, compositions, and kits disclosed herein may be used for thediagnosis, prognosis, and/or monitoring the status or outcome of acancer in a subject. In some embodiments, the diagnosing, predicting,and/or monitoring the status or outcome of a cancer comprisesdetermining the malignancy or malignant potential of the cancer ortumor. Alternatively, the diagnosing, predicting, and/or monitoring thestatus or outcome of a cancer comprises determining the stage of thecancer. The diagnosing, predicting, and/or monitoring the status oroutcome of a cancer can comprise determining the tumor grade.Alternatively, the diagnosing, predicting, and/or monitoring the statusor outcome of a cancer comprises assessing the risk of developing acancer. In some embodiments, the diagnosing, predicting, and/ormonitoring the status or outcome of a cancer includes assessing the riskof cancer recurrence. In some embodiments, diagnosing, predicting,and/or monitoring the status or outcome of a cancer may comprisedetermining the efficacy of treatment.

In some embodiments, diagnosing, predicting, and/or monitoring thestatus or outcome of a cancer may comprise determining a therapeuticregimen. Determining a therapeutic regimen may comprise administering ananti-cancer therapeutic. Alternatively, determining the treatment forthe cancer may comprise modifying a therapeutic regimen. Modifying atherapeutic regimen may comprise increasing, decreasing, or terminatinga therapeutic regimen.

In some instances, the methods disclosed herein can diagnose, prognose,and/or monitor the status or outcome of a cancer in a subject with anaccuracy of at least about 50%. In other instances, the methodsdisclosed herein can diagnose, prognose, and/or monitor the status oroutcome of a cancer in a subject with an accuracy of at least about 60%.The methods disclosed herein can diagnose, prognose, and/or monitor thestatus or outcome of a cancer in a subject with an accuracy of at leastabout 65%. Alternatively, the methods disclosed herein can diagnose,prognose, and/or monitor the status or outcome of a cancer in a subjectwith an accuracy of at least about 70%. In some instances, the methodsdisclosed herein can diagnose, prognose, and/or monitor the status oroutcome of a cancer in a subject with an accuracy of at least about 75%.In other instances, the methods disclosed herein can diagnose, prognose,and/or monitor the status or outcome of a cancer in a subject with anaccuracy of at least about 80%. The methods disclosed herein candiagnose, prognose, and/or monitor the status or outcome of a cancer ina subject with an accuracy of at least about 85%. Alternatively, themethods disclosed herein can diagnose, prognose, and/or monitor thestatus or outcome of a cancer in a subject with an accuracy of at leastabout 90%. The methods disclosed herein can diagnose, prognose, and/ormonitor the status or outcome of a cancer in a subject with an accuracyof at least about 95%.

The invention also encompasses any of the methods disclosed herein wherethe sensitivity is at least about 45%. In some embodiments, thesensitivity is at least about 50%. In some embodiments, the sensitivityis at least about 55%. In some embodiments, the sensitivity is at leastabout 60%. In some embodiments, the sensitivity is at least about 65%.In some embodiments, the sensitivity is at least about 70%. In someembodiments, the sensitivity is at least about 75%. In some embodiments,the sensitivity is at least about 80%. In some embodiments, thesensitivity is at least about 85%. In some embodiments, the sensitivityis at least about 90%. In some embodiments, the sensitivity is at leastabout 95%.

The invention also encompasses any of the methods disclosed herein wherethe expression level determines the status or outcome of a cancer in thesubject with at least about 45% specificity. In some embodiments, theexpression level determines the status or outcome of a cancer in thesubject with at least about 50% specificity. In some embodiments, theexpression level determines the status or outcome of a cancer in thesubject with at least about 55% specificity. In some embodiments, theexpression level determines the status or outcome of a cancer in thesubject with at least about 60% specificity. In some embodiments, theexpression level determines the status or outcome of a cancer in thesubject with at least about 65% specificity. In some embodiments, theexpression level determines the status or outcome of a cancer in thesubject with at least about 70% specificity. In some embodiments, theexpression level determines the status or outcome of a cancer in thesubject with at least about 75% specificity. In some embodiments, theexpression level determines the status or outcome of a cancer in thesubject with at least about 80% specificity. In some embodiments, theexpression level determines the status or outcome of a cancer in thesubject with at least about 85% specificity. In some embodiments, theexpression level determines the status or outcome of a cancer in thesubject with at least about 90% specificity. In some embodiments, theexpression level determines the status or outcome of a cancer in thesubject with at least about 95% specificity.

Cancer

The systems, compositions and methods disclosed herein may be used todiagnosis, monitor and/or predict the status or outcome of a cancer.Generally, a cancer is characterized by the uncontrolled growth ofabnormal cells anywhere in a body. The abnormal cells may be termedcancer cells, malignant cells, or tumor cells. Many cancers and theabnormal cells that compose the cancer tissue are further identified bythe name of the tissue that the abnormal cells originated from (forexample, breast cancer, lung cancer, colon cancer, prostate cancer,pancreatic cancer, thyroid cancer). Cancer is not confined to humans;animals and other living organisms can get cancer.

In some instances, the cancer may be malignant. Alternatively, thecancer may be benign. The cancer may be a recurrent and/or refractorycancer. Most cancers can be classified as a carcinoma, sarcoma,leukemia, lymphoma, myeloma, or a central nervous system cancer.

The cancer may be a sarcoma. Sarcomas are cancers of the bone,cartilage, fat, muscle, blood vessels, or other connective or supportivetissue. Sarcomas include, but are not limited to, bone cancer,fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignanthemangioendothelioma, malignant schwannoma, bilateral vestibularschwannoma, osteosarcoma, soft tissue sarcomas (e.g. alveolar soft partsarcoma, angiosarcoma, cystosarcoma phylloides, dermatofibrosarcoma,desmoid tumor, epithelioid sarcoma, extraskeletal osteosarcoma,fibrosarcoma, hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma,leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignantfibrous histiocytoma, neurofibrosarcoma, rhabdomyosarcoma, and synovialsarcoma).

Alternatively, the cancer may be a carcinoma. Carcinomas are cancersthat begin in the epithelial cells, which are cells that cover thesurface of the body, produce hormones, and make up glands. By way ofnon-limiting example, carcinomas include breast cancer, pancreaticcancer, lung cancer, colon cancer, colorectal cancer, rectal cancer,kidney cancer, bladder cancer, stomach cancer, prostate cancer, livercancer, ovarian cancer, brain cancer, vaginal cancer, vulvar cancer,uterine cancer, oral cancer, penic cancer, testicular cancer, esophagealcancer, skin cancer, cancer of the fallopian tubes, head and neckcancer, gastrointestinal stromal cancer, adenocarcinoma, cutaneous orintraocular melanoma, cancer of the anal region, cancer of the smallintestine, cancer of the endocrine system, cancer of the thyroid gland,cancer of the parathyroid gland, cancer of the adrenal gland, cancer ofthe urethra, cancer of the renal pelvis, cancer of the ureter, cancer ofthe endometrium, cancer of the cervix, cancer of the pituitary gland,neoplasms of the central nervous system (CNS), primary CNS lymphoma,brain stem glioma, and spinal axis tumors. In some instances, the canceris a skin cancer, such as a basal cell carcinoma, squamous, melanoma,nonmelanoma, or actinic (solar) keratosis. Preferably, the cancer is aprostate cancer. Alternatively, the cancer may be a thyroid cancer. Thecancer can be a pancreatic cancer. In some instances, the cancer is abladder cancer.

In some instances, the cancer is a lung cancer. Lung cancer can start inthe airways that branch off the trachea to supply the lungs (bronchi) orthe small air sacs of the lung (the alveoli). Lung cancers includenon-small cell lung carcinoma (NSCLC), small cell lung carcinoma, andmesotheliomia. Examples of NSCLC include squamous cell carcinoma,adenocarcinoma, and large cell carcinoma. The mesothelioma may be acancerous tumor of the lining of the lung and chest cavity (pleura) orlining of the abdomen (peritoneum). The mesothelioma may be due toasbestos exposure. The cancer may be a brain cancer, such as aglioblastoma.

Alternatively, the cancer may be a central nervous system (CNS) tumor.CNS tumors may be classified as gliomas or nongliomas. The glioma may bemalignant glioma, high grade glioma, diffuse intrinsic pontine glioma.Examples of gliomas include astrocytomas, oligodendrogliomas (ormixtures of oligodendroglioma and astocytoma elements), and ependymomas.Astrocytomas include, but are not limited to, low-grade astrocytomas,anaplastic astrocytomas, glioblastoma multiforme, pilocytic astrocytoma,pleomorphic xanthoastrocytoma, and subependymal giant cell astrocytoma.Oligodendrogliomas include low-grade oligodendrogliomas (oroligoastrocytomas) and anaplastic oligodendriogliomas. Nongliomasinclude meningiomas, pituitary adenomas, primary CNS lymphomas, andmedulloblastomas. In some instances, the cancer is a meningioma.

The cancer may be leukemia. The leukemia may be an acute lymphocyticleukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, orchronic myelocytic leukemia. Additional types of leukemias include hairycell leukemia, chronic myelomonocytic leukemia, and juvenilemyelomonocytic-leukemia.

In some instances, the cancer is a lymphoma. Lymphomas are cancers ofthe lymphocytes and may develop from either B or T lymphocytes. The twomajor types of lymphoma are Hodgkin's lymphoma, previously known asHodgkin's disease, and non-Hodgkin's lymphoma. Hodgkin's lymphoma ismarked by the presence of the Reed-Sternberg cell. Non-Hodgkin'slymphomas are all lymphomas which are not Hodgkin's lymphoma.Non-Hodgkin lymphomas may be indolent lymphomas and aggressivelymphomas. Non-Hodgkin's lymphomas include, but are not limited to,diffuse large B cell lymphoma, follicular lymphoma, mucosa-associatedlymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma,mantle cell lymphoma, Burkitt's lymphoma, mediastinal large B celllymphoma, Waldenström macroglobulinemia, nodal marginal zone B celllymphoma (NMZL), splenic marginal zone lymphoma (SMZL), extranodalmarginal zone B cell lymphoma, intravascular large B cell lymphoma,primary effusion lymphoma, and lymphomatoid granulomatosis.

Cancer Staging

Diagnosing, predicting, or monitoring a status or outcome of a cancermay comprise determining the stage of the cancer. Generally, the stageof a cancer is a description (usually numbers I to IV with IV havingmore progression) of the extent the cancer has spread. The stage oftentakes into account the size of a tumor, how deeply it has penetrated,whether it has invaded adjacent organs, how many lymph nodes it hasmetastasized to (if any), and whether it has spread to distant organs.Staging of cancer can be used as a predictor of survival, and cancertreatment may be determined by staging. Determining the stage of thecancer may occur before, during, or after treatment. The stage of thecancer may also be determined at the time of diagnosis.

Cancer staging can be divided into a clinical stage and a pathologicstage. Cancer staging may comprise the TNM classification. Generally,the TNM Classification of Malignant Tumours (TNM) is a cancer stagingsystem that describes the extent of cancer in a patient's body. T maydescribe the size of the tumor and whether it has invaded nearby tissue,N may describe regional lymph nodes that are involved, and M maydescribe distant metastasis (spread of cancer from one body part toanother). In the TNM (Tumor, Node, Metastasis) system, clinical stageand pathologic stage are denoted by a small “c” or “p” before the stage(e.g., cT3N1M0 or pT2N0).

Often, clinical stage and pathologic stage may differ. Clinical stagemay be based on all of the available information obtained before asurgery to remove the tumor. Thus, it may include information about thetumor obtained by physical examination, radiologic examination, andendoscopy. Pathologic stage can add additional information gained byexamination of the tumor microscopically by a pathologist. Pathologicstaging can allow direct examination of the tumor and its spread,contrasted with clinical staging which may be limited by the fact thatthe information is obtained by making indirect observations at a tumorwhich is still in the body. The TNM staging system can be used for mostforms of cancer.

Alternatively, staging may comprise Ann Arbor staging. Generally, AnnArbor staging is the staging system for lymphomas, both in Hodgkin'slymphoma (previously called Hodgkin's disease) and Non-Hodgkin lymphoma(abbreviated NHL). The stage may depend on both the place where themalignant tissue is located (as located with biopsy, CT scanning andincreasingly positron emission tomography) and on systemic symptoms dueto the lymphoma (“B symptoms”: night sweats, weight loss of >10% orfevers). The principal stage may be determined by location of the tumor.Stage I may indicate that the cancer is located in a single region,usually one lymph node and the surrounding area. Stage I often may nothave outward symptoms. Stage II can indicate that the cancer is locatedin two separate regions, an affected lymph node or organ and a secondaffected area, and that both affected areas are confined to one side ofthe diaphragm—that is, both are above the diaphragm, or both are belowthe diaphragm. Stage III often indicates that the cancer has spread toboth sides of the diaphragm, including one organ or area near the lymphnodes or the spleen. Stage IV may indicate diffuse or disseminatedinvolvement of one or more extralymphatic organs, including anyinvolvement of the liver, bone marrow, or nodular involvement of thelungs.

Modifiers may also be appended to some stages. For example, the lettersA, B, E, X, or S can be appended to some stages. Generally, A or B mayindicate the absence of constitutional (B-type) symptoms is denoted byadding an “A” to the stage; the presence is denoted by adding a “B” tothe stage. E can be used if the disease is “extranodal” (not in thelymph nodes) or has spread from lymph nodes to adjacent tissue. X isoften used if the largest deposit is >10 cm large (“bulky disease”), orwhether the mediastinum is wider than ⅓ of the chest on a chest X-ray. Smay be used if the disease has spread to the spleen.

The nature of the staging may be expressed with CS or PS. CS may denotethat the clinical stage as obtained by doctor's examinations and tests.PS may denote that the pathological stage as obtained by exploratorylaparotomy (surgery performed through an abdominal incision) withsplenectomy (surgical removal of the spleen).

Therapeutic Regimens

Diagnosing, predicting, or monitoring a status or outcome of a cancermay comprise treating a cancer or preventing a cancer progression. Inaddition, diagnosing, predicting, or monitoring a status or outcome of acancer may comprise identifying or predicting responders to ananti-cancer therapy. In some instances, diagnosing, predicting, ormonitoring may comprise determining a therapeutic regimen. Determining atherapeutic regimen may comprise administering an anti-cancer therapy.Alternatively, determining a therapeutic regimen may comprise modifying,recommending, continuing or discontinuing an anti-cancer regimen. Insome instances, if the sample expression patterns are consistent withthe expression pattern for a known disease or disease outcome, theexpression patterns can be used to designate one or more treatmentmodalities (e.g., therapeutic regimens, anti-cancer regimen). Ananti-cancer regimen may comprise one or more anti-cancer therapies.Examples of anti-cancer therapies include surgery, chemotherapy,radiation therapy, immunotherapy/biological therapy, photodynamictherapy.

Surgical oncology uses surgical methods to diagnose, stage, and treatcancer, and to relieve certain cancer-related symptoms. Surgery may beused to remove the tumor (e.g., excisions, resections, debulkingsurgery), reconstruct a part of the body (e.g., restorative surgery),and/or to relieve symptoms such as pain (e.g., palliative surgery).Surgery may also include cryosurgery. Cryosurgery (also calledcryotherapy) may use extreme cold produced by liquid nitrogen (or argongas) to destroy abnormal tissue. Cryosurgery can be used to treatexternal tumors, such as those on the skin. For external tumors, liquidnitrogen can be applied directly to the cancer cells with a cotton swabor spraying device. Cryosurgery may also be used to treat tumors insidethe body (internal tumors and tumors in the bone). For internal tumors,liquid nitrogen or argon gas may be circulated through a hollowinstrument called a cryoprobe, which is placed in contact with thetumor. An ultrasound or MRI may be used to guide the cryoprobe andmonitor the freezing of the cells, thus limiting damage to nearbyhealthy tissue. A ball of ice crystals may form around the probe,freezing nearby cells. Sometimes more than one probe is used to deliverthe liquid nitrogen to various parts of the tumor. The probes may be putinto the tumor during surgery or through the skin (percutaneously).After cryosurgery, the frozen tissue thaws and may be naturally absorbedby the body (for internal tumors), or may dissolve and form a scab (forexternal tumors).

Chemotherapeutic agents may also be used for the treatment of cancer.Examples of chemotherapeutic agents include alkylating agents,anti-metabolites, plant alkaloids and terpenoids, vinca alkaloids,podophyllotoxin, taxanes, topoisomerase inhibitors, and cytotoxicantibiotics. Cisplatin, carboplatin, and oxaliplatin are examples ofalkylating agents. Other alkylating agents include mechlorethamine,cyclophosphamide, chlorambucil, ifosfamide. Alkylating agents may impaircell function by forming covalent bonds with the amino, carboxyl,sulfhydryl, and phosphate groups in biologically important molecules.Alternatively, alkylating agents may chemically modify a cell's DNA.

Anti-metabolites are another example of chemotherapeutic agents.Anti-metabolites may masquerade as purines or pyrimidines and mayprevent purines and pyrimidines from becoming incorporated in to DNAduring the “S” phase (of the cell cycle), thereby stopping normaldevelopment and division. Antimetabolites may also affect RNA synthesis.Examples of metabolites include azathioprine and mercaptopurine.

Alkaloids may be derived from plants and block cell division may also beused for the treatment of cancer. Alkyloids may prevent microtubulefunction. Examples of alkaloids are vinca alkaloids and taxanes. Vincaalkaloids may bind to specific sites on tubulin and inhibit the assemblyof tubulin into microtubules (M phase of the cell cycle). The vincaalkaloids may be derived from the Madagascar periwinkle, Catharanthusroseus (formerly known as Vinca rosea). Examples of vinca alkaloidsinclude, but are not limited to, vincristine, vinblastine, vinorelbine,or vindesine. Taxanes are diterpenes produced by the plants of the genusTaxus (yews). Taxanes may be derived from natural sources or synthesizedartificially. Taxanes include paclitaxel (Taxol) and docetaxel(Taxotere). Taxanes may disrupt microtubule function. Microtubules areessential to cell division, and taxanes may stabilize GDP-bound tubulinin the microtubule, thereby inhibiting the process of cell division.Thus, in essence, taxanes may be mitotic inhibitors. Taxanes may also beradiosensitizing and often contain numerous chiral centers.

Alternative chemotherapeutic agents include podophyllotoxin.Podophyllotoxin is a plant-derived compound that may help with digestionand may be used to produce cytostatic drugs such as etoposide andteniposide. They may prevent the cell from entering the G1 phase (thestart of DNA replication) and the replication of DNA (the S phase).

Topoisomerases are essential enzymes that maintain the topology of DNA.Inhibition of type I or type II topoisomerases may interfere with bothtranscription and replication of DNA by upsetting proper DNAsupercoiling. Some chemotherapeutic agents may inhibit topoisomerases.For example, some type I topoisomerase inhibitors include camptothecins:irinotecan and topotecan. Examples of type II inhibitors includeamsacrine, etoposide, etoposide phosphate, and teniposide.

Another example of chemotherapeutic agents is cytotoxic antibiotics.Cytotoxic antibiotics are a group of antibiotics that are used for thetreatment of cancer because they may interfere with DNA replicationand/or protein synthesis. Cytotoxic antiobiotics include, but are notlimited to, actinomycin, anthracyclines, doxorubicin, daunorubicin,valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, andmitomycin.

In some instances, the anti-cancer treatment may comprise radiationtherapy. Radiation can come from a machine outside the body(external-beam radiation therapy) or from radioactive material placed inthe body near cancer cells (internal radiation therapy, more commonlycalled brachytherapy). Systemic radiation therapy uses a radioactivesubstance, given by mouth or into a vein that travels in the blood totissues throughout the body.

External-beam radiation therapy may be delivered in the form of photonbeams (either x-rays or gamma rays). A photon is the basic unit of lightand other forms of electromagnetic radiation. An example ofexternal-beam radiation therapy is called 3-dimensional conformalradiation therapy (3D-CRT). 3D-CRT may use computer software andadvanced treatment machines to deliver radiation to very preciselyshaped target areas. Many other methods of external-beam radiationtherapy are currently being tested and used in cancer treatment. Thesemethods include, but are not limited to, intensity-modulated radiationtherapy (IMRT), image-guided radiation therapy (IGRT), Stereotacticradiosurgery (SRS), Stereotactic body radiation therapy (SBRT), andproton therapy.

Intensity-modulated radiation therapy (IMRT) is an example ofexternal-beam radiation and may use hundreds of tiny radiationbeam-shaping devices, called collimators, to deliver a single dose ofradiation. The collimators can be stationary or can move duringtreatment, allowing the intensity of the radiation beams to changeduring treatment sessions. This kind of dose modulation allows differentareas of a tumor or nearby tissues to receive different doses ofradiation. IMRT is planned in reverse (called inverse treatmentplanning). In inverse treatment planning, the radiation doses todifferent areas of the tumor and surrounding tissue are planned inadvance, and then a high-powered computer program calculates therequired number of beams and angles of the radiation treatment. Incontrast, during traditional (forward) treatment planning, the numberand angles of the radiation beams are chosen in advance and computerscalculate how much dose may be delivered from each of the planned beams.The goal of IMRT is to increase the radiation dose to the areas thatneed it and reduce radiation exposure to specific sensitive areas ofsurrounding normal tissue.

Another example of external-beam radiation is image-guided radiationtherapy (IGRT). In IGRT, repeated imaging scans (CT, MRI, or PET) may beperformed during treatment. These imaging scans may be processed bycomputers to identify changes in a tumor's size and location due totreatment and to allow the position of the patient or the plannedradiation dose to be adjusted during treatment as needed. Repeatedimaging can increase the accuracy of radiation treatment and may allowreductions in the planned volume of tissue to be treated, therebydecreasing the total radiation dose to normal tissue.

Tomotherapy is a type of image-guided IMRT. A tomotherapy machine is ahybrid between a CT imaging scanner and an external-beam radiationtherapy machine. The part of the tomotherapy machine that deliversradiation for both imaging and treatment can rotate completely aroundthe patient in the same manner as a normal CT scanner. Tomotherapymachines can capture CT images of the patient's tumor immediately beforetreatment sessions, to allow for very precise tumor targeting andsparing of normal tissue.

Stereotactic radiosurgery (SRS) can deliver one or more high doses ofradiation to a small tumor. SRS uses extremely accurate image-guidedtumor targeting and patient positioning. Therefore, a high dose ofradiation can be given without excess damage to normal tissue. SRS canbe used to treat small tumors with well-defined edges. It is mostcommonly used in the treatment of brain or spinal tumors and brainmetastases from other cancer types. For the treatment of some brainmetastases, patients may receive radiation therapy to the entire brain(called whole-brain radiation therapy) in addition to SRS. SRS requiresthe use of a head frame or other device to immobilize the patient duringtreatment to ensure that the high dose of radiation is deliveredaccurately.

Stereotactic body radiation therapy (SBRT) delivers radiation therapy infewer sessions, using smaller radiation fields and higher doses than3D-CRT in most cases. SBRT may treat tumors that lie outside the brainand spinal cord. Because these tumors are more likely to move with thenormal motion of the body, and therefore cannot be targeted asaccurately as tumors within the brain or spine, SBRT is usually given inmore than one dose. SBRT can be used to treat small, isolated tumors,including cancers in the lung and liver. SBRT systems may be known bytheir brand names, such as the CyberKnife®.

In proton therapy, external-beam radiation therapy may be delivered byproton. Protons are a type of charged particle. Proton beams differ fromphoton beams mainly in the way they deposit energy in living tissue.Whereas photons deposit energy in small packets all along their paththrough tissue, protons deposit much of their energy at the end of theirpath (called the Bragg peak) and deposit less energy along the way. Useof protons may reduce the exposure of normal tissue to radiation,possibly allowing the delivery of higher doses of radiation to a tumor.

Other charged particle beams such as electron beams may be used toirradiate superficial tumors, such as skin cancer or tumors near thesurface of the body, but they cannot travel very far through tissue.

Internal radiation therapy (brachytherapy) is radiation delivered fromradiation sources (radioactive materials) placed inside or on the body.Several brachytherapy techniques are used in cancer treatment.Interstitial brachytherapy may use a radiation source placed withintumor tissue, such as within a prostate tumor. Intracavitarybrachytherapy may use a source placed within a surgical cavity or a bodycavity, such as the chest cavity, near a tumor. Episcleralbrachytherapy, which may be used to treat melanoma inside the eye, mayuse a source that is attached to the eye. In brachytherapy, radioactiveisotopes can be sealed in tiny pellets or “seeds.” These seeds may beplaced in patients using delivery devices, such as needles, catheters,or some other type of carrier. As the isotopes decay naturally, theygive off radiation that may damage nearby cancer cells. Brachytherapymay be able to deliver higher doses of radiation to some cancers thanexternal-beam radiation therapy while causing less damage to normaltissue.

Brachytherapy can be given as a low-dose-rate or a high-dose-ratetreatment. In low-dose-rate treatment, cancer cells receive continuouslow-dose radiation from the source over a period of several days. Inhigh-dose-rate treatment, a robotic machine attached to delivery tubesplaced inside the body may guide one or more radioactive sources into ornear a tumor, and then removes the sources at the end of each treatmentsession. High-dose-rate treatment can be given in one or more treatmentsessions. An example of a high-dose-rate treatment is the MammoSite®system. Bracytherapy may be used to treat patients with breast cancerwho have undergone breast-conserving surgery.

The placement of brachytherapy sources can be temporary or permanent.For permanent brachytherapy, the sources may be surgically sealed withinthe body and left there, even after all of the radiation has been givenoff. In some instances, the remaining material (in which the radioactiveisotopes were sealed) does not cause any discomfort or harm to thepatient. Permanent brachytherapy is a type of low-dose-ratebrachytherapy. For temporary brachytherapy, tubes (catheters) or othercarriers are used to deliver the radiation sources, and both thecarriers and the radiation sources are removed after treatment.Temporary brachytherapy can be either low-dose-rate or high-dose-ratetreatment. Brachytherapy may be used alone or in addition toexternal-beam radiation therapy to provide a “boost” of radiation to atumor while sparing surrounding normal tissue.

In systemic radiation therapy, a patient may swallow or receive aninjection of a radioactive substance, such as radioactive iodine or aradioactive substance bound to a monoclonal antibody. Radioactive iodine(131I) is a type of systemic radiation therapy commonly used to helptreat cancer, such as thyroid cancer. Thyroid cells naturally take upradioactive iodine. For systemic radiation therapy for some other typesof cancer, a monoclonal antibody may help target the radioactivesubstance to the right place. The antibody joined to the radioactivesubstance travels through the blood, locating and killing tumor cells.For example, the drug ibritumomab tiuxetan (Zevalin®) may be used forthe treatment of certain types of B-cell non-Hodgkin lymphoma (NHL). Theantibody part of this drug recognizes and binds to a protein found onthe surface of B lymphocytes. The combination drug regimen oftositumomab and iodine I 131 tositumomab (Bexxar®) may be used for thetreatment of certain types of cancer, such as NHL. In this regimen,nonradioactive tositumomab antibodies may be given to patients first,followed by treatment with tositumomab antibodies that have 131Iattached. Tositumomab may recognize and bind to the same protein on Blymphocytes as ibritumomab. The nonradioactive form of the antibody mayhelp protect normal B lymphocytes from being damaged by radiation from131I.

Some systemic radiation therapy drugs relieve pain from cancer that hasspread to the bone (bone metastases). This is a type of palliativeradiation therapy. The radioactive drugs samarium-153-lexidronam(Quadramet®) and strontium-89 chloride (Metastron®) are examples ofradiopharmaceuticals may be used to treat pain from bone metastases.

Biological therapy (sometimes called immunotherapy, biotherapy, orbiological response modifier (BRM) therapy) uses the body's immunesystem, either directly or indirectly, to fight cancer or to lessen theside effects that may be caused by some cancer treatments. Biologicaltherapies include interferons, interleukins, colony-stimulating factors,monoclonal antibodies, vaccines, gene therapy, and nonspecificimmunomodulating agents.

Interferons (IFNs) are types of cytokines that occur naturally in thebody. Interferon alpha, interferon beta, and interferon gamma areexamples of interferons that may be used in cancer treatment.

Like interferons, interleukins (ILs) are cytokines that occur naturallyin the body and can be made in the laboratory. Many interleukins havebeen identified for the treatment of cancer. For example, interleukin-2(IL-2 or aldesleukin), interleukin 7, and interleukin 12 have may beused as an anti-cancer treatment. IL-2 may stimulate the growth andactivity of many immune cells, such as lymphocytes, that can destroycancer cells. Interleukins may be used to treat a number of cancers,including leukemia, lymphoma, and brain, colorectal, ovarian, breast,kidney and prostate cancers.

Colony-stimulating factors (CSFs) (sometimes called hematopoietic growthfactors) may also be used for the treatment of cancer. Some examples ofCSFs include, but are not limited to, G-CSF (filgrastim) and GM-CSF(sargramostim). CSFs may promote the division of bone marrow stem cellsand their development into white blood cells, platelets, and red bloodcells. Bone marrow is critical to the body's immune system because it isthe source of all blood cells. Because anticancer drugs can damage thebody's ability to make white blood cells, red blood cells, andplatelets, stimulation of the immune system by CSFs may benefit patientsundergoing other anti-cancer treatment, thus CSFs may be combined withother anti-cancer therapies, such as chemotherapy. CSFs may be used totreat a large variety of cancers, including lymphoma, leukemia, multiplemyeloma, melanoma, and cancers of the brain, lung, esophagus, breast,uterus, ovary, prostate, kidney, colon, and rectum.

Another type of biological therapy includes monoclonal antibodies (MOABsor MoABs). These antibodies may be produced by a single type of cell andmay be specific for a particular antigen. To create MOABs, human cancercells may be injected into mice. In response, the mouse immune systemcan make antibodies against these cancer cells. The mouse plasma cellsthat produce antibodies may be isolated and fused with laboratory-growncells to create “hybrid” cells called hybridomas. Hybridomas canindefinitely produce large quantities of these pure antibodies, orMOABs. MOABs may be used in cancer treatment in a number of ways. Forinstance, MOABs that react with specific types of cancer may enhance apatient's immune response to the cancer. MOABs can be programmed to actagainst cell growth factors, thus interfering with the growth of cancercells.

MOABs may be linked to other anti-cancer therapies such aschemotherapeutics, radioisotopes (radioactive substances), otherbiological therapies, or other toxins. When the antibodies latch ontocancer cells, they deliver these anti-cancer therapies directly to thetumor, helping to destroy it. MOABs carrying radioisotopes may alsoprove useful in diagnosing certain cancers, such as colorectal, ovarian,and prostate.

Rituxan® (rituximab) and Herceptin® (trastuzumab) are examples of MOABsthat may be used as a biological therapy. Rituxan may be used for thetreatment of non-Hodgkin lymphoma. Herceptin can be used to treatmetastatic breast cancer in patients with tumors that produce excessamounts of a protein called HER2. Alternatively, MOABs may be used totreat lymphoma, leukemia, melanoma, and cancers of the brain, breast,lung, kidney, colon, rectum, ovary, prostate, and other areas.

Cancer vaccines are another form of biological therapy. Cancer vaccinesmay be designed to encourage the patient's immune system to recognizecancer cells. Cancer vaccines may be designed to treat existing cancers(therapeutic vaccines) or to prevent the development of cancer(prophylactic vaccines). Therapeutic vaccines may be injected in aperson after cancer is diagnosed. These vaccines may stop the growth ofexisting tumors, prevent cancer from recurring, or eliminate cancercells not killed by prior treatments. Cancer vaccines given when thetumor is small may be able to eradicate the cancer. On the other hand,prophylactic vaccines are given to healthy individuals before cancerdevelops. These vaccines are designed to stimulate the immune system toattack viruses that can cause cancer. By targeting these cancer-causingviruses, development of certain cancers may be prevented. For example,cervarix and gardasil are vaccines to treat human papilloma virus andmay prevent cervical cancer. Therapeutic vaccines may be used to treatmelanoma, lymphoma, leukemia, and cancers of the brain, breast, lung,kidney, ovary, prostate, pancreas, colon, and rectum. Cancer vaccinescan be used in combination with other anti-cancer therapies.

Gene therapy is another example of a biological therapy. Gene therapymay involve introducing genetic material into a person's cells to fightdisease. Gene therapy methods may improve a patient's immune response tocancer. For example, a gene may be inserted into an immune cell toenhance its ability to recognize and attack cancer cells. In anotherapproach, cancer cells may be injected with genes that cause the cancercells to produce cytokines and stimulate the immune system.

In some instances, biological therapy includes nonspecificimmunomodulating agents. Nonspecific immunomodulating agents aresubstances that stimulate or indirectly augment the immune system.Often, these agents target key immune system cells and may causesecondary responses such as increased production of cytokines andimmunoglobulins. Two nonspecific immunomodulating agents used in cancertreatment are bacillus Calmette-Guerin (BCG) and levamisole. BCG may beused in the treatment of superficial bladder cancer following surgery.BCG may work by stimulating an inflammatory, and possibly an immune,response. A solution of BCG may be instilled in the bladder. Levamisoleis sometimes used along with fluorouracil (5-FU) chemotherapy in thetreatment of stage III (Dukes' C) colon cancer following surgery.Levamisole may act to restore depressed immune function.

Photodynamic therapy (PDT) is an anti-cancer treatment that may use adrug, called a photosensitizer or photosensitizing agent, and aparticular type of light. When photosensitizers are exposed to aspecific wavelength of light, they may produce a form of oxygen thatkills nearby cells. A photosensitizer may be activated by light of aspecific wavelength. This wavelength determines how far the light cantravel into the body. Thus, photosensitizers and wavelengths of lightmay be used to treat different areas of the body with PDT.

In the first step of PDT for cancer treatment, a photosensitizing agentmay be injected into the bloodstream. The agent may be absorbed by cellsall over the body but may stay in cancer cells longer than it does innormal cells. Approximately 24 to 72 hours after injection, when most ofthe agent has left normal cells but remains in cancer cells, the tumorcan be exposed to light. The photosensitizer in the tumor can absorb thelight and produces an active form of oxygen that destroys nearby cancercells. In addition to directly killing cancer cells, PDT may shrink ordestroy tumors in two other ways. The photosensitizer can damage bloodvessels in the tumor, thereby preventing the cancer from receivingnecessary nutrients. PDT may also activate the immune system to attackthe tumor cells.

The light used for PDT can come from a laser or other sources. Laserlight can be directed through fiber optic cables (thin fibers thattransmit light) to deliver light to areas inside the body. For example,a fiber optic cable can be inserted through an endoscope (a thin,lighted tube used to look at tissues inside the body) into the lungs oresophagus to treat cancer in these organs. Other light sources includelight-emitting diodes (LEDs), which may be used for surface tumors, suchas skin cancer. PDT is usually performed as an outpatient procedure. PDTmay also be repeated and may be used with other therapies, such assurgery, radiation, or chemotherapy.

Extracorporeal photopheresis (ECP) is a type of PDT in which a machinemay be used to collect the patient's blood cells. The patient's bloodcells may be treated outside the body with a photosensitizing agent,exposed to light, and then returned to the patient. ECP may be used tohelp lessen the severity of skin symptoms of cutaneous T-cell lymphomathat has not responded to other therapies. ECP may be used to treatother blood cancers, and may also help reduce rejection aftertransplants.

Additionally, photosensitizing agent, such as porfimer sodium orPhotofrin®, may be used in PDT to treat or relieve the symptoms ofesophageal cancer and non-small cell lung cancer. Porfimer sodium mayrelieve symptoms of esophageal cancer when the cancer obstructs theesophagus or when the cancer cannot be satisfactorily treated with lasertherapy alone. Porfimer sodium may be used to treat non-small cell lungcancer in patients for whom the usual treatments are not appropriate,and to relieve symptoms in patients with non-small cell lung cancer thatobstructs the airways. Porfimer sodium may also be used for thetreatment of precancerous lesions in patients with Barrett esophagus, acondition that can lead to esophageal cancer.

Laser therapy may use high-intensity light to treat cancer and otherillnesses. Lasers can be used to shrink or destroy tumors orprecancerous growths. Lasers are most commonly used to treat superficialcancers (cancers on the surface of the body or the lining of internalorgans) such as basal cell skin cancer and the very early stages of somecancers, such as cervical, penile, vaginal, vulvar, and non-small celllung cancer.

Lasers may also be used to relieve certain symptoms of cancer, such asbleeding or obstruction. For example, lasers can be used to shrink ordestroy a tumor that is blocking a patient's trachea (windpipe) oresophagus. Lasers also can be used to remove colon polyps or tumors thatare blocking the colon or stomach.

Laser therapy is often given through a flexible endoscope (a thin,lighted tube used to look at tissues inside the body). The endoscope isfitted with optical fibers (thin fibers that transmit light). It isinserted through an opening in the body, such as the mouth, nose, anus,or vagina. Laser light is then precisely aimed to cut or destroy atumor.

Laser-induced interstitial thermotherapy (LITT), or interstitial laserphotocoagulation, also uses lasers to treat some cancers. LITT issimilar to a cancer treatment called hyperthermia, which uses heat toshrink tumors by damaging or killing cancer cells. During LITT, anoptical fiber is inserted into a tumor. Laser light at the tip of thefiber raises the temperature of the tumor cells and damages or destroysthem. LITT is sometimes used to shrink tumors in the liver.

Laser therapy can be used alone, but most often it is combined withother treatments, such as surgery, chemotherapy, or radiation therapy.In addition, lasers can seal nerve endings to reduce pain after surgeryand seal lymph vessels to reduce swelling and limit the spread of tumorcells.

Lasers used to treat cancer may include carbon dioxide (CO2) lasers,argon lasers, and neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers.Each of these can shrink or destroy tumors and can be used withendoscopes. CO2 and argon lasers can cut the skin's surface withoutgoing into deeper layers. Thus, they can be used to remove superficialcancers, such as skin cancer. In contrast, the Nd:YAG laser is morecommonly applied through an endoscope to treat internal organs, such asthe uterus, esophagus, and colon. Nd:YAG laser light can also travelthrough optical fibers into specific areas of the body during LITT.Argon lasers are often used to activate the drugs used in PDT.

EXPERIMENTAL

The following examples are provided in order to demonstrate and furtherillustrate certain preferred embodiments and aspects of the presentinvention and are not to be construed as limiting the scope thereof.

Example 1 A. Methods

Methods Summary

All prostate tissue samples were obtained from the University ofMichigan Specialized Program Of Research Excellence (S.P.O.R.E.) usingan IRB-approved informed consent protocol. Next generation sequencingand library preparation was performed as previously described (Maher etal., Proc Natl Acad Sci USA 106 (30), 12353 (2009)). Uniquely mappingsequencing reads were aligned with TopHat and sequencing data for allsamples was merged. Ab initio transcriptome assembly was performed byaligning sequences with TopHat and using uniquely mapped read positionsto build transcripts with Cufflinks. Informatics approaches were used torefine the assembly and predict expressed transcriptional units.Unannotated transcripts were nominated based upon their absence in theUCSC, RefSeq, ENSEMBL, ENCODE, and Vega databases. Differentialexpression was determined using the Significance Analysis of Microarrays(SAM) algorithm (Tusher et al., Proc Natl Acad Sci USA 98 (9), 5116(2001)) on log 2 mean expression in benign, cancer, and metastaticsamples. Cancer outlier profile analysis (COPA) was performed aspreviously described (Tomlins et al., Science 310 (5748), 644 (2005))with slight modifications. PCR experiments were performed according tostandard protocols, and RACE was performed with the GeneRacer Kit(Invitrogen) according to manufacturer's instructions. ChIP-seq data wasobtained from previously published data (Yu et al., Cancer Cell 17 (5),443). siRNA knockdown was performed with custom siRNA oligos (Dharmacon)with Oligofectamine (Invitrogen). Transmembrane invasion assays wereperformed with Matrigel (BD Biosciences) and cell proliferation assayswere performed by cell count with a Coulter counter. Urine analyses wereperformed as previously described (Laxman et al., Cancer Res 68 (3), 645(2008)) with minor modifications.

Cell Lines and Tissues

The benign immortalized prostate cell line RWPE as well as PC3, Du145,LNCaP, VCaP, 22Rv1, CWR22, C4-2B, NCI-660, MDA PCa 2b, WPMY-1, andLAPC-4 prostate cell lines were obtained from the American Type CultureCollection (Manassas, Va.). Benign non-immortalized prostate epithelialcells (PrEC) and prostate smooth muscle cells (PrSMC) were obtained fromLonza (Basel, Switzerland). Cell lines were maintained using standardmedia and conditions. For androgen treatment experiments, LNCaP and VCaPcells were grown in androgen depleted media lacking phenol red andsupplemented with 10% charcoal-stripped serum and 1%penicillin-streptomycin. After 48 hours, cells were treated with 5 nMmethyltrienolone (R1881, NEN Life Science Products) or an equivalentvolume of ethanol. Cells were harvested for RNA at 6, 24, and 48 hourspost-treatment. Prostate tissues were obtained from the radicalprostatectomy series and Rapid Autopsy Program at the University ofMichigan tissue core. These programs are part of the University ofMichigan Prostate Cancer Specialized Program Of Research Excellence(S.P.O.R.E.). All tissue samples were collected with informed consentunder an Institutional Review Board (IRB) approved protocol at theUniversity of Michigan.

PC3, Du145, LNCaP, 22Rv1, and CRW22 cells were grown in RPMI 1640(Invitrogen) and supplemented with 10% fetal bovine serum (FBS) and 1%penicillin-streptomycin. LNCaP CDS parent cells were grown in RPMI 1640lacking phenol red (Invitrogen) supplemented with 10% charcoal-dextranstripped FBS (Invitrogen) and 1% penicillin-streptomycin. LNCaP CDS 1,2, and 3 are androgen-independent subclones derived from extended cellculture in androgendepleted media. VCaP and WPMY-1 cells were grown inDMEM (Invitrogen) and supplemented with 10% fetal bovine serum (FBS)with 1% penicillin-streptomycin. NCI-H660 cells were grown in RPMI 1640supplemented with 0.005 mg/ml insulin, 0.01 mg/ml transferring, 30 nMsodium selenite, 10 nM hydrocortisone, 10 nM beta-estradiol, 5% FBS andan extra 2 mM of L-glutamine (for a final concentration of 4 mM). MDAPCa 2b cells were grown in F-12K medium (Invitrogen) supplemented with20% FBS, 25 ng/ml cholera toxin, 10 ng/ml EGF, 0.005 mMphosphoethanolamine, 100 pg/ml hydrocortisone, 45 nM selenious acid, and0.005 mg/ml insulin. LAPC-4 cells were grown in Iscove's media(Invitrogen) supplemented with 10% FBS and 1 nM R1881. C4-2B cells weregrown in 80% DMEM supplemented with 20% F12, 5% FBS, 3 g/L NaCo₃, 5μg/ml insulin, 13.6 pg/ml triiodothyonine, 5 μg/ml transferrin, 0.25μg/ml biotin, and 25 μg/ml adenine. PrEC cells were grown in PrEGMsupplemented with 2 ml BPE, 0.5 ml hydrocortisone, 0.5 ml EGF, 0.5 mlepinephrine, 0.5 ml transferring, 0.5 ml insulin, 0.5 ml retinoic acid,and 0.5 ml triiodothyronine, as part of the PrEGM BulletKit (Lonza).PrSMC cells were grown in SmGM-2 media supplemented with 2 ml BPE, 0.5ml hydrocortisone, 0.5 ml EGF, 0.5 ml epinephrine, 0.5 ml transferring,0.5 ml insulin, 0.5 ml retinoic acid, and 0.5 ml triiodothyronine, aspart of the SmGM-2 BulletKit (Lonza).

RNA-Seq Library Preparation.

Next generation sequencing of RNA was performed on 21 prostate celllines, 20 benign adjacent prostates, 47 localized tumors, and 14metastatic tumors according to Illumina's protocol using 2 μg of RNA.RNA integrity was measured using an Agilent 2100 Bioanalyzer, and onlysamples with a RIN score >7.0 were advanced for library generation. RNAwas poly-A+ selected using the OligodT beads provided by Ilumina andfragmented with the Ambion Fragmentation Reagents kit (Ambion, Austin,Tex.). cDNA synthesis, end-repair, A-base addition, and ligation of theIllumina PCR adaptors (single read or paired-end where appropriate) wereperformed according to Illumina's protocol. Libraries were thensize-selected for 250-300 bp cDNA fragments on a 3.5% agarose gel andPCR-amplified using Phusion DNA polymerase (Finnzymes) for 15-18 PCRcycles. PCR products were then purified on a 2% agarose gel andgel-extracted. Library quality was credentialed by assaying each libraryon an Agilent 2100 Bioanalyzer of product size and concentration.Libraries were sequenced as 36-45mers on an Illumina Genome Analyzer Ior Genome Analyzer II flowcell according to Illumina's protocol. Allsingle read samples were sequenced on a Genome Analyzer I, and allpaired-end samples were sequenced on a Genome Analyzer II.

RNA Isolation and cDNA Synthesis

Total RNA was isolated using Trizol and an RNeasy Kit (Invitrogen) withDNase I digestion according to the manufacturer's instructions. RNAintegrity was verified on an Agilent Bioanalyzer 2100 (AgilentTechnologies, Palo Alto, Calif.). cDNA was synthesized from total RNAusing Superscript III (Invitrogen) and random primers (Invitrogen).

Quantitative Real-Time PCR

Quantitative Real-time PCR (qPCR) was performed using Power SYBR GreenMastermix (Applied Biosystems, Foster City, Calif.) on an AppliedBiosystems 7900HT Real-Time PCR System. All oligonucleotide primers wereobtained from Integrated DNA Technologies (Coralville, Iowa). Thehousekeeping gene, GAPDH, was used as a loading control. Fold changeswere calculated relative to GAPDH and normalized to the median value ofthe benign samples.

Reverse-Transcription PCR

Reverse-transcription PCR (RT-PCR) was performed for primer pairs usingPlatinum Taq High Fidelity polymerase (Invitrogen). PCR products wereresolved on a 2% agarose gel. PCR products were either sequenceddirectly (if only a single product was observed) or appropriate gelproducts were extracted using a Gel Extraction kit (Qiagen) and clonedinto per4-TOPO vectors (Invitrogen). PCR products were bidirectionallysequenced at the University of Michigan Sequencing Core using eithergene-specific primers or M13 forward and reverse primers for cloned PCRproducts. All oligonucleotide primers were obtained from Integrated DNATechnologies (Coralville, Iowa).

RNA-Ligase-Mediated Rapid Amplification of cDNA Ends (RACE)

5′ and 3′ RACE was performed using the GeneRacer RLM-RACE kit(Invitrogen) according to the manufacturer's instructions. RACE PCRproducts were obtained using Platinum Taq High Fidelity polymerase(Invitrogen), the supplied GeneRacer primers, and appropriategene-specific primers. RACEPCR products were separated on a 2% agarosegels. Gel products were extracted with a Gel Extraction kit (Qiagen),cloned into per4-TOPO vectors (Invitrogen), and sequencedbidirectionally using M13 forward and reverse primers at the Universityof Michigan Sequencing Core. At least three colonies were sequenced forevery gel product that was purified.

Paired-End Next-Generation Sequencing of RNA

2 μg total RNA was selected for polyA+ RNA using Sera-Mag oligo(dT)beads (Thermo Scientific), and paired-end next-generation sequencinglibraries were prepared as previously described (Maher et al., supra)using Illumina-supplied universal adaptor oligos and PCR primers(Illumina). Samples were sequenced in a single lane on an IlluminaGenome Analyzer II flowcell using previously described protocols (Maheret al., supra). 36-45 mer paired-end reads were according to theprotocol provided by Illumina.

siRNA Knockdown Studies

Cells were plated in 100 mM plates at a desired concentration andtransfected with 20 μM experimental siRNA oligos or non-targetingcontrols twice, at 12 hours and 36 hours post-plating. Knockdowns wereperformed with Oligofectamine and Optimem. Knockdown efficiency wasdetermined by qPCR. 72 hours post-transfection, cells were trypsinized,counted with a Coulter counter, and diluted to 1 million cells/mL. Forproliferation assays, 200,000 cells were plated in 24-well plates andgrown in regular media. 48 and 96 hours post-plating, cells wereharvested and counted using a Coulter counter. For invasion assays,Matrigel was diluted 1:4 in serum-free media and 100 μL of the dilutedMatrigel was applied to a Boyden chamber transmembrane insert andallowed to settle overnight at 37° C. 200,000 cells suspended inserum-free media were applied per insert and 500 μL of serum-containingmedia was placed in the bottom of the Boyden (fetal bovine serumfunctioning as a chemoattractant). Cells were allowed to invade for 48hours, at which time inserts were removed and noninvading cells andMatrigel were gently removed with a cotton swab. Invading cells werestained with crystal violet for 15 minutes and air-dried. Forcolorimetric assays, the inserts were treated with 200 μl of 10% aceticacid and the absorbance at 560 nm was measured using aspectrophotometer. For WST-1 assays, 20,000 cells were plated into96-well plates and grown in 100 μL of serum-containing media. 48 and 96hours post-plating, cells were measured for viability by adding 10 μL ofWST-1 reagent to the cell media, incubating for 2 hours at 37° C. andmeasuring the absorbance at 450 nM using a spectrophotomer.

Urine qPCR

Urine samples were collected from 120 patients with informed consentfollowing a digital rectal exam before either needle biopsy or radicalprostatectomy at the University of Michigan with Institutional ReviewBoard approval as described previously (Laxman et al., Cancer Res 68(3), 645 (2008)). Isolation of RNA from urine and TransPlex wholetranscriptome amplification were performed as described previously(Laxman et al., Neoplasia 8 (10), 885 (2006)). qPCR on urine samples wasperformed for KLK3 (PSA), TMPRSS2-ERG, GAPDH, PCA3, PCAT-1 and PCAT-14using Power SYBR Mastermix (Applied Biosystems) as described above. RawCt values were extracted and normalized in the following manner. First,samples with GAPDH Ct values >25 or KLK3 Ct values >30 were removed fromanalysis to ensure sufficient prostate cell collection, leaving 10⁸samples for analysis. The GAPDH and KLK3 raw Ct values were average foreach sample. ΔCt analysis was performed by measuring each value againstthe average of CtGAPDH and CtKLK3, and ΔCt values were normalized to themedian ΔCt of the benign samples. Fold change was then calculated at2−ΔCt. Samples were considered to be prostate cancer ifhistopathological analysis observed cancer or if the TMPRSS2-ERGtranscript achieved a Ct value <37. Benign samples were defined assamples with normal histology and TMPRSS2-ERG transcript Ct values >37.

Statistical Analyses for Experimental Studies

All data are presented as means±s.e.m. All experimental assays wereperformed in duplicate or triplicate.

Bioinformatics Analyses

To achieve an ab initio prediction of the prostate cancer transcriptomeexisting publicly tools for mapping, assembly, and quantification oftranscripts were supplemented with additional informatics filteringsteps to enrich the results for the most robust transcript predictions(FIG. 6 a). Transcripts were then identified and classified by comparingthem against gene annotation databases (FIG. 6 b). Details of thebioinformatics analyses are provided below.

Mapping Reads with TopHat

Reads were aligned using TopHat v1.0.13 (Feb. 5, 2010) (Trapnell et al.,Bioinformatics 25, 1105-11 (2009)), a gapped aligner capable ofdiscovering splice junctions ab initio. Briefly, TopHat aligns reads tothe human genome using Bowtie (Langmead et al., Genome Biol 10, R25(2009)) to determine a set of “coverage islands” that may representputative exons. TopHat uses these exons as well as the presence of GT-AGgenomic splicing motifs to build a second set of reference sequencesspanning exon-exon junctions. The unmapped reads from the initial genomealignment step are then remapped against this splice junction referenceto discover all the junction-spanning reads in the sample. TopHatoutputs the reads that successfully map to either the genome or thesplice junction reference in SAM format for further analysis. For thisstudy a maximum intron size of 500 kb, corresponding to over 99.98% ofRefSeq (Wheeler et al. Nucleic Acids Res 28, 10-4 (2000)) introns wasused. For sequencing libraries the insert size was determined using anAgilent 2100 Bioanalyzer prior to data analysis, and it was found thatthis insert size agreed closely with software predictions. An insertsize standard deviation of 20 bases was chosen in order to match themost common band size cut from gels during library preparation. Intotal, 1.723 billion fragments were generated from 201 lanes ofsequencing on the Illumina Genome Analyzer and Illumina Genome AnalyzerII. Reads were mapped to the human genome (hg18) downloaded from theUCSC genome browser website (Karolchik et al., Nucleic Acids Res 31,51-4 (2003); Kent et al., Genome Res 12, 996-1006 (2002)). 1.418 billionunique alignments were obtained, including 114.4 million splicejunctions for use in transcriptome assembly. Reads with multiplealignments with less than two mismatches were discarded.

Ab Initio Assembly and Quantification with Cufflinks

Aligned reads from TopHat were assembled into sample-specifictranscriptomes with Cufflinks version 0.8.2 (Mar. 26, 2010) (Trapnell etal., Nat Biotechnol 28, 511-5). Cufflinks assembles exonic andsplice-junction reads into transcripts using their alignmentcoordinates. To limit false positive assemblies a maximum introniclength of 300 kb, corresponding to the 99.93% percentile of knownintrons was used. After assembling transcripts, Cufflinks computesisoform-level abundances by finding a parsimonious allocation of readsto the transcripts within a locus. Transcripts with abundance less than15% of the major transcript in the locus, and minor isoforms withabundance less than 5% of the major isoform were filtered. Defaultsettings were used for the remaining parameters.

The Cufflinks assembly stage yielded a set of transcript annotations foreach of the sequenced libraries. The transcripts were partitioned bychromosome and the Cuffcompare utility provided by Cufflinks was used tomerge the transcripts into a combined set of annotations. TheCuffcompare program performs a union of all transcripts by mergingtranscripts that share all introns and exons. The 5′ and 3′ exons oftranscripts were allowed to vary by up to 100 nt during the comparisonprocess.

Distinguishing Transcripts from Background Signal

Cuffcompare reported a total of 8.25 million distinct transcripts.Manual inspection of these transcripts in known protein coding generegions indicated that most of the transcripts were likely to be poorquality reconstructions of overlapping larger transcripts. Also, many ofthe transcripts were unspliced and had a total length smaller than thesize selected fragment length of approximately ˜250 nt. Furthermore,many of these transcripts were only present in a single sample. Astatistical classifier to predict transcripts over background signal wasdesigned to identify highly recurrent transcripts that may be altered inprostate cancer. AceView (Thierry-Mieg et al. Genome Biol 7 Suppl 1, S121-14 (2006)) were used. For each transcript predicted by Cufflinks thefollowing statistics were collected: length (bp), number of exons,recurrence (number of samples in which the transcript was predicted),95th percentile of abundance (measured in Fragments per Kilobase perMillion reads (FPKM)) across all samples, and uniqueness of genomic DNAharboring the transcript transcript (measured using the Rosettauniqueness track from UCSC (Rhead et al. 2010. Nucleic Acids Res 38,D613-9). Using this information, recursive partitioning and regressiontrees in R (package rpart) were used to predict, for each transcript,whether its expression patterns and structural properties resembledthose of annotated genes. Classification was performed independently foreach chromosome in order to incorporate the effect of gene densityvariability on expression thresholds. Transcripts that were notclassified as annotated genes were discarded, and the remainder weresubjected to additional analysis and filtering steps. By examining thedecision tree results it was observed that the 95th percentile ofexpression across all samples as well as the recurrence of eachtranscript were most frequently the best predictors of expressed versusbackground transcripts (FIG. 7).

Refinement of Transcript Fragments

The statistical classifier predicted a total 2.88 million (34.9%)transcript fragments as “expressed” transcripts. A program was developedto extend and merge intron-redundant transcripts to produce a minimumset of transcripts that describes the assemblies produced by Cufflinks.The merging step produced a total of 123,554 independent transcripts.Tanscript abundance levels were re-computed for these revisedtranscripts in Reads per Kilobase per Million (RPKM) units. Theseexpression levels were used for the remainder of the study. Severaladditional filtering steps were used to isolate the most robusttranscripts. First, transcripts with a total length less than 200 ntwere discarded. Single exon transcripts with greater than 75% overlap toanother longer transcript were also discarded. Transcripts that lacked acompletely unambiguous genomic DNA stretch of at least 40 nt were alsoremoved. Genomic uniqueness was measured using the Rosetta uniquenesstrack downloaded from the UCSC genome browser website. Transcripts thatwere not present in at least 5% of the cohort (>5 samples) at more than5.0 RPKM were retained.

In certain instances transcripts were observed that were interrupted bypoorly mappable genomic regions. Additionally, for low abundance genesfragmentation due to the lack of splice junction or paired-end readevidence needed to connect nearby fragments were observed. Thedifference in the Pearson correlation between expression of randomlychosen exons on the same transcript versus expression of spatiallyproximal exons on different transcripts was measured and it was foundthat in the cohort, a Pearson correlation >0.8 had a positive predictivevalue (PPV) of >95% for distinct exons to be part of the sametranscript. Using this criteria, hierarchical agglomerative clusteringto extend transcript fragments into larger transcriptional units wasperformed. Pairs of transcripts further than 100 kb apart, transcriptson opposite strands, and overlapping transcripts were not considered forclustering. Groups of correlated transcripts were merged, and introns<40 nt in length were removed.

Comparison with Gene Annotation Databases

The 44,534 transcripts produced by the bioinformatics pipeline wereclassified by comparison with a comprehensive list of “annotated”transcripts from UCSC, RefSeq, ENCODE, Vega, and Ensembl. First,transcripts corresponding to processed pseudogenes were separated. Thiswas done to circumvent a known source of bias in the TopHat readaligner. TopHat maps reads to genomic DNA in its first step,predisposing exon-exon junction reads to align to their splicedretroposed pseudogene homologues. Next, transcripts with >1 bp ofoverlap with at least one annotated gene on the correct strand weredesignated “annotated”, and the remainder were deemed “unannotated”.Transcripts with no overlap with protein coding genes were subdividedinto intronic, intergenic, or partially intronic antisense categoriesbased on their relative genomic locations.

Informatics Filtering of Unspliced Pre-mRNA Isoforms

An increase in the percentage of intronic transcripts in the assemblyrelative to known intronic ncRNAs was observed. This led to theobservation that in many cases unspliced pre mRNAs appear at sufficientlevels to escape the filtering steps employed by Cufflinks during theassembly stage. Intronic and antisense transcripts that were correlated(Pearson correlation >0.5) to their overlapping protein coding geneswere removed. This effectively removed transcripts within genes such asPCA3 and HPN that were obvious premRNA artifacts, while leaving trulynovel intronic transcripts—such as those within FBXL7 and CDH13—intact.These steps produced a consensus set of 35,415 transcripts supportinglong polyadenylated RNA molecules in human prostate tissues and celllines. Per chromosome transcript counts closely mirrored knowntranscript databases (Table 2), indicating that the informaticsprocedures employed compensate well for gene density variability acrosschromosomes. Overall a similar number of transcripts as present in theeither the RefSeq or UCSC databases (Wheeler et al. Nucleic Acids Res28, 10-4 (2000)) were detected.

Coding Potential Analysis

To analyze coding potential, DNA sequences for each transcript wereextracted and searched for open reading frames (ORFs) using thetxCdsPredict program from the UCSC source tool set (Kent et al. GenomeRes 12, 996-1006 (2002)). This program produces a score corresponding tothe protein coding capacity of a given sequence, and scores >800 are˜90% predictive of protein coding genes. This threshold was used tocount transcripts with coding potential, and found only 5 of 6,641unannotated genes with scores >800, compared with 1,669 of 25,414protein coding transcripts. Additionally, it was observed that proteincoding genes possess consistently longer ORFs than either unannotated orannotated ncRNA transcripts, indicating that the vast majority of theunannotated transcripts represent ncRNAs (FIG. 10).

Separation of Transcripts into Repetitive and Non-Repetitive Categories

To separate transcripts into “repeat” and “non-repeat” transcripts, thegenomic DNA corresponding to the transcript exons was extracted and thefraction of repeat-masked nucleotides in each sequence were calculated.For the designation of repeat classes, RepMask 3.2.7 UCSC Genome Browsertrack (Kent, supra) was used. It was observed that transcripts enrichedwith repetitive DNA tended to be poorly conserved and lacked ChIP-seqmarks of active chromatin (FIG. 12). Transcripts containing >25%repetitive DNA (FIG. 11) were separated for the purposes of the ChIP-seqand conservation analyses discussed below.

Conservation Analysis

The SiPhy package (Garber et al. Bioinformatics 25, i54-62 (2009)) wasused to estimate the locate rate of variation (w) of all non-repetitivetranscript exons across 29 placental mammals. The program was run asdescribed on the SiPhy website.

ChIP-Seq Datasets

Published ChIP-Seq datasets for H3K4me1, H3K4me2, H3K4me3, AcetylatedH3, Pan-H3, and H3K36me3 were used (Yu et al. Cancer Cell 17, 443-54).These data are publicly available through the NCBI Geo Omnibus (GEOGSM353632). The raw ChIP-Seq data was analyzed using MACS34 (H3K4me1,H3K4me2, H3K4me3, Acetylated H3, and Pan-H3) or SICER35 (H3K36me3) peakfinder programs using default settings. These peak finders were usedbased upon their preferential suitability to detect different types ofhistone modifications (Pepke et al., Nat Methods 6, S22-32 (2009)). TheH3K4me3-H3K36me3 chromatin signature used to identify lincRNAs wasdetermined from the peak coordinates by associating each H3K4me3 peakwith the closest H3K36me3-enriched region up to a maximum of 10 kb away.The enhancer signature (H3K4me1 but not H3K4me3) was determined bysubtracting the set of overlapping H3K4me3 peaks from the entire set ofH3K4me1 peaks. These analyses were performed with the bx-pythonlibraries distributed as part of the Galaxy bioinformaticsinfrastructure.

Differential Expression Analysis

To predict differentially expressed transcripts a matrix oflog-transformed, normalized RPKM expression values was prepared by usingthe base 2 logarithm after adding 0.1 to all RPKM values. The data werefirst centered by subtracting the median expression of the benignsamples for each transcript. The Significance Analysis of Microarrays(SAM) method (Tusher et al., Proc Natl Acad Sci USA 98, 5116-21 (2001))with 250 permutations of the Tusher et al. S0 selection method was usedto predict differentially expressed genes. A delta value correspondingto the 90th percentile FDR desired for individual analyses was used. TheMultiExperiment Viewer application (Chu et al., Genome Biol 9, R118(2008)) was used to run SAM and generate heatmaps. It was confirmed thatthe results matched expected results through comparison with microarraysand known prostate cancer biomarkers.

Outlier Analysis

A modified COPA analysis was performed on the 81 tissue samples in thecohort. RPKM expression values were used and shifted by 1.0 in order toavoid division by zero. The COPA analysis had the following steps(MacDonald & Ghosh, Bioinformatics 22, 2950-1 (2006); Tomlins et al.Science 310, 644-8 (2005)): 1) gene expression values were mediancentered, using the median expression value for the gene across the allsamples in the cohort. This sets the gene's median to zero. 2) Themedian absolute deviation (MAD) was calculated for each gene, and theneach gene expression value was scaled by its MAD. 3) The 80, 85, 90, 98percentiles of the transformed expression values were calculated foreach gene and the average of those four values was taken. Then, geneswere rank ordered according to this “average percentile”, whichgenerated a list of outliers genes arranged by importance. 4) Finally,genes showing an outlier profile in the benign samples were discarded.Six novel transcripts ranked as both outliers anddifferentially-expressed genes in the analyses. These six were manuallyclassified either as differentially-expressed or outlier status based onwhat each individual's distribution across samples indicated.

Repeat Enrichment Analysis

To assess the enrichment of repetitive elements in the assembly, 100random permutations of the transcript positions on the same chromosomeand strand were generated. To mirror the original constraints used tonominate transcripts it was ensured that permuted transcript positionscontained a uniquely mappable stretch of genomic DNA at least 50 ntlong. To account for the effects of mappability difficulties, each exonwas padded by ±0 bp, 50 bp, 100 bp, or 500 bp of additional genomicsequence before intersecting the exons with repeat elements in theRepeatMasker 3.2.7 database. It was observed that padding by more than50 bp did not improve enrichment results and padded exons by ±50 bp insubsequent analyses and tests. Finally, the Shapiro-Wilk test fornormality was performed and it was verified that the number of matchesto highly abundant repetitive element types was approximately normallydistributed.

B. Results

Prostate Cancer Transcriptome Sequencing

Transcriptome sequencing (RNA-Seq) was performed on 21 prostate celllines, 20 benign adjacent prostates (benign), 47 localized tumors (PCA),and 14 metastatic tumors (MET). A total of 201 RNA-Seq libraries fromthis cohort were sequenced yielding a total of 1.41 billion mappedreads, with a median 4.70 million mapped reads per sample (Table 1 forsample information).

To analyze these data a method for ab initio transcriptome assembly toreconstruct transcripts and transcript abundance levels was used (FIG. 6and Table 2) (Trapnell et al., NatBiotechnol 28 (5), 511; Trapnell etal., Bioinformatics 25 (9), 1105 (2009)). Sample-specific transcriptomeswere predicted and individual predication were merged into a consensustranscriptome and the most robust transcripts were retained (FIG. 7).The ab initio transcriptome assembly and subsequent refinement stepsyielded 35,415 distinct transcriptional loci (see FIG. 8 for examples).

The assembled transcriptome was compared to the UCSC, Ensembl, Refseq,Vega, and ENCODE gene databases to identify and categorize transcripts.While the majority of the transcripts (77.3%) corresponded to annotatedprotein coding genes (72.1%) and noncoding RNAs (5.2%), a significantpercentage (19.8%) lacked any overlap and were designated “unannotated”(FIG. 1 a). These included partially intronic antisense (2.44%), totallyintronic (12.1%), and intergenic transcripts (5.25%). These resultsagree with previous data indicating that large fractions of thetranscriptome represent unannotated transcription (Birney et al., Nature447 (7146), 799 (2007); Carninci et al., Science 309 (5740), 1559 (2005)and that significant percentages of genes may harbor related antisensetranscripts (He et al., Science 322 (5909), 1855 (2008); Yelin et al.,Nat Biotechnol 21 (4), 379 (2003)). Due to the added complexity ofcharacterizing antisense or partially intronic transcripts withoutstrand-specific RNA-Seq libraries, studies focused on totally intronicand intergenic transcripts.

Characterization of Novel Transcripts

Global characterization of novel transcripts corroborated previousreports that they are relatively poorly conserved and more lowlyexpressed than protein coding genes (Guttman et al., Nat Biotechnol 28(5), 503; Guttman et al., Nature 458 (7235), 223 (2009)). Expressionlevels of unannotated prostate cancer transcripts were consistentlyhigher than randomly permuted controls, but lower than annotated ncRNAsor protein coding genes (FIG. 1 b). Unannotated transcripts also showedless overlap with known expressed sequence tags (ESTs) thanprotein-coding genes but more than randomly permuted controls (FIG. 5).Unannotated transcripts showed a clear but subtle increase inconservation over control genomic intervals (novel intergenictranscripts p=2.7×10−4±0.0002 for 0.4<ω<0.8; novel intronic transcriptsp=2.6×10−5±0.0017 for 0<ω<0.4, FIG. 1 c). Only a small subset of novelintronic transcripts showed increased conservation (FIG. 1 c insert),but this conservation was quite profound. By contrast, a larger numberof novel intergenic transcripts showed more mild increases inconservation. Finally, analysis of coding potential revealed that only 5of 6,144 transcripts harbored a high quality open reading frame (ORF),indicating that the overwhelming majority of these transcripts representncRNAs (FIG. 10).

Next, published prostate cancer ChIP-Seq data for two prostate celllines (Yu et al., Cancer Cell 17 (5), 443; VCaP and LNCaP was used inorder to interrogate the overlap of unannotated transcripts with histonemodifications supporting active transcription (H3K4me1, H3K4me2,H3K4me3, H3K36me3, Acetyl-H3 and RNA polymerase II, see Table 3).Because unannotated ncRNAs showed two clear subtypes, repeat-associatedand non-repeats (FIG. 11 and discussed below), it was contemplated thatthese two subtypes may display distinct histone modifications as notedin previous research (Day et al., Genome Biol 11 (6), R69). Whereasnon-repeat transcripts showed strong enrichment for histone marks ofactive transcription at their putative transcriptional start sites(TSSs), repeat-associated transcripts showed virtually no enrichment(FIG. 12), and for the remaining ChIP-Seq analyses non-repeattranscripts only were considered. In this set of unannotatedtranscripts, strong enrichment for histone modifications characterizingTSSs and active transcription, including H3K4me2, H3K4me3, Acetyl-H3 andRNA Polymerase II (FIG. 1 d-g) but not H3K4me1 was observed, whichcharacterizes enhancer regions (FIGS. 13 and 14). Intergenic ncRNAsperformed much better in these analyses than intronic ncRNAs (FIG. 1d-g). To elucidate global changes in transcript abundance betweenprostate cancer and benign tissues, differential expression wasperformed analysis for all transcripts. 836 genesdifferentially-expressed between benign and PCA samples (FDR <0.01) werefound, with protein-coding genes constituting 82.8% of alldifferentially-expressed genes (FIG. 1 h and Table 4). This categorycontained the most significant transcripts, including numerous knownprostate cancer genes such as AMACR32 and Hepsin (Dhanasekaran et al.,Nature 412 (6849), 822 (2001)). Annotated ncRNAs represented 7.4% ofdifferentially-expressed genes, including the ncRNA PCA334, whichresides within an intron of the PRUNE2 gene and ranked #4 overall (12.2fold change; adj. p<2×10-4, Wilcoxon rank sum test, Benjamini-Hochbergcorrection) (FIG. 8). Finally, 9.8% of differentially-expressed genescorresponded to unannotated ncRNAs, including 3.2% within gene intronsand 6.6% in intergenic regions, indicating that these species contributesignificantly to the complexity of the prostate cancer transcriptome.

Dysregulation of Unannotated Non-Coding RNAs

Recent reports of functional long intervening non-coding RNAs(Dhanasekaran et al., Nature 412 (6849), 822 (2001); Gupta et al.,Nature 464 (7291), 1071; Rinn et al., Cell 129 (7), 1311 (2007); Guttmanet al., Nature 458 (7235), 223 (2009)) (lincRNAs) in intergenic regionsled to an exploration of intergenic ncRNAs further. A total of 1859unannotated intergenic RNAs were found throughout the human genome. Thepresent invention is not limited to a particular mechanism. Indeed, anunderstanding of the mechanism is not necessary to practice the presentinvention. Nonetheless it is contemplated that this is an underestimatedue to the inability to detect small RNAs eliminated by the ˜250 bp sizeselection performed during RNA-Seq library generation (Methods).Overall, novel intergenic RNAs resided closer to protein-coding genesthan protein-coding genes do to each other (the median distance to thenearest protein-coding gene is 4292 kb for novel genes and 8559 kb forprotein-coding genes, FIG. 2 a). For instance, if two protein-codinggenes, Gene A and Gene B, are separated by the distance AB, then thefurthest an unannotated ncRNA can be from both of them is 0.5*AB, whichis exactly what was observed (4292/8559=0.501). Supporting thisobservation, 34.1% of unannotated transcripts are located ≧10 kb fromthe nearest protein-coding gene. As an example, the Chr15q arm wasvisualized using the Circos program. Eighty-nine novel intergenictranscripts were nominated across this chromosomal region, includingseveral differentially-expressed loci centromeric to TLE3 (FIG. 2 b)which were validated by PCR in prostate cancer cell lines (FIG. 15). Afocused analysis of the 1859 novel intergenic RNAs yielded 106 that weredifferentially expressed in localized tumors (FDR <0.05; FIG. 2 c).These Prostate Cancer Associated Transcripts (PCATs) were rankedaccording to their fold change in localized tumor versus benign tissue(Tables 5 and 6).

Similarly, performing a modified cancer outlier profile analysis (COPA)on the RNA-Seq dataset re-discovered numerous known prostate canceroutliers, such as ERG7, ETV17, SPINK135, and CRISP336,37, and nominatednumerous unannotated ncRNAs as outliers (FIG. 2 d and Tables 6 and 7).Merging the results from the differential expression and COPA analysesresulted in a set of 121 unannotated transcripts that accuratelydiscriminated benign, localized tumor, and metastatic prostate samplesby unsupervised clustering (FIG. 2 c). These data provide evidence thatPCATs serve as biomarkers for prostate cancer and novel prostate cancersubtypes. Clustering analyses using novel ncRNA outliers also providedisease subtypes (FIG. 16).

Confirmation and Tissue-Specificity of ncRNAs

Validation studies were performed on 14 unannotated expressed regions,including ones both included and not present in the list ofdifferentially expressed transcripts. Reverse transcription PCR(RT-PCR)and quantitative real-time PCR (qPCR) experiments demonstrated a ˜78%(11/14) validation rate in predicted cell line models for bothtranscript identity and expression level (FIG. 17). Next, threetranscripts (PCAT-109, PCAT-14, and PCAT-43) selectively upregulated inprostate cancer compared to normal prostate were examined. From thesequencing data, each genomic loci shows significantly increasedexpression in prostate cancer and metastases, except for PCAT-14, whichappears absent in metastases (FIG. 3 a-c). PCAT-109 also ranks as the #5best outlier in prostate cancer, just ahead of ERG (FIG. 2 d and Table6). qPCR on a cohort of 14 benign prostates, 47 tumors, and 10metastases confirmed expression of these transcripts (FIG. 3 a-c). Allthree appear to be prostate-specific, with no expression seen in breastor lung cancer cell lines or in 19 normal tissue types (Table 8). Thistissue specificity was not necessarily due to regulation by androgensignaling, as only PCAT-14 expression was induced by treatment ofandrogen responsive VCaP and LNCaP cells with the synthetic androgenR1881, consistent with previous data from this genomic locus (FIG. 18)(Tomlins et al., Nature 448 (7153), 595 (2007); Stavenhagen et al., Cell55 (2), 247 (1988)). PCAT-14, but not PCAT-109 or PCAT-43, also showeddifferential expression when tested on a panel of matched tumor-normalsamples, indicating that this transcript, which is comprised of anendogenous retrovirus in the HERV-K family (Bannert and Kurth, Proc NatlAcad Sci USA 101 Suppl 2, 14572 (2004)), can be used as a somatic markerfor prostate cancer (FIG. 19). 5′ and 3′ rapid amplification of cDNAends (RACE) at this locus revealed the presence of individual viralprotein open reading frames (ORFs) and a transcript splicing togetherindividual ORF 5′ untranslated region (UTR) sequences (FIG. 20). It wasobserved that the top-ranked intergenic ncRNA resided in the chromosome8q24 gene desert nearby to the c-Myc oncogene. This ncRNA, termedPCAT-1, is located on the edge of the prostate cancer susceptibilityregion 240-43 (FIG. 4 a) and is about 0.5 Mb away from c-Myc. Thistranscript is supported by clear peaks in H3K4me3, Acetyl-H3, and RNApolymerase II ChIP-Seq data (FIG. 4 b). The exon-exon junction in celllines was validated by RT-PCR and Sanger sequencing of the junction(FIG. 4 c), and 5′ and 3′ RACE was performed to elucidate transcriptstructure (FIG. 4 d). By this analysis, PCAT-1 is a mariner familytransposase (Oosumi et al., Nature 378 (6558), 672 (1995); Robertson etal., Nat Genet. 12 (4), 360 (1996)) interrupted by an Aluretrotransposon and regulated by a viral long terminal repeat (LTR)promoter region (FIG. 4 d and FIG. 21). By qPCR, PCAT-1 expression isspecific to prostate tissue, with striking upregulation in prostatecancers and metastases compared to benign prostate tissue (FIG. 4 e).PCAT-1 ranks as the second best overall prostate cancer biomarker, justbehind AMACR (Table 3), indicating that this transcript is a powerfuldiscriminator of this disease. Matched tumor normal pairs similarlyshowed marked upregulation in the matched tumor samples (FIG. 4 f). RNAinterference (RNAi) was performed in VCaP cells using custom siRNAstargeting PCAT-1 sequences and no change in the cell proliferation orinvasion upon PCAT-1 knockdown was observed (FIG. 22)

Selective Re-Expression of Repetitive Elements in Cancer

The presence of repetitive elements in PCAT-1 led to an exploration ofrepetitive elements. Repetitive elements, such as Alu and LINE-1retrotransposons, are broadly known to be degenerate in humans (Oosumiet al, supra; Robertson et al., supra; Cordaux et al., Nat Rev Genet. 10(10), 691 (2009), with only ˜100 LINE-1 elements (out of 12˜500,000)showing possible retrotransposon activity (Brouha et al., Proc Natl AcadSci U S A 100 (9), 5280 (2003)). While transcription of these elementsis frequently repressed through DNA methylation and repressive chromatinmodifications (Slotkin and Martienssen, Nat Rev Genet. 8 (4), 272(2007)), in cancer widespread hypomethylation has been reported (Cho etal., J Pathol 211 (3), 269 (2007); Chalitchagorn et al., Oncogene 23(54), 8841 (2004); Yegnasubramanian et al., Cancer Res 68 (21), 8954(2008)). Moreover, recent evidence indicates that these elements havefunctional roles in both normal biology (Kunarso et al., Nat. Genet.)and cancer (Lin et al., Cell 139 (6), 1069 (2009)), even if theirsequences have mutated away from their evolutionary ancestral sequence(Chow et al., Cell 141 (6), 956). To date, only RNA-Seq platforms enablediscovery and quantification of specific transposable elements expressedin cancer. As described above, it was observed that >50% of unannotatedexons in the assembly overlap with at least one repetitive element (FIG.11). Since these elements pose mappability challenges when performingtranscriptome assembly with unique reads, these loci typically appear as“mountain ranges” of expression, with uniquely mappable regions formingpeaks of expression separated by unmappable “ravines” (FIGS. 23 and 24).PCR and Sanger sequencing experiments were performed to confirm thatthese transposable elements of low mappability are expressed as part ofthese loci (FIGS. 23 and 24). To probe this observation further, theexons from unannotated transcripts in the assembly, with the addition ofthe flanking 50, 100, or 500 bp of additional genomic sequence to the 5′and 3′ end of the exons were generated, the overlap of these intervalswith repetitive elements to randomly permuted genomic intervals ofsimilar sizes was performed. A highly significant enrichment forrepetitive elements in the dataset was observed (OR 2.82 (95% CI2.68-2.97), p<10-100). Examination of the individual repetitive elementclasses revealed a specific enrichment for SINE elements, particularlyAlus (p≦2×10-16, Tables 10 and 11). A subset of LINE-1 and Alutransposable elements demonstrate marked differential expression in asubset of prostate cancer tumors (FIG. 25). One locus on chromosome 2(also highlighted in FIG. 3 b) is a 500+ kb region with numerousexpressed transposable elements (FIG. 26). This locus, termed SecondChromosome Locus Associated with Prostate-1 (SChLAP1), harborstranscripts that perform extremely well in outlier analyses for prostatecancer (Tables 6 and 7). PCAT-109, discussed above, is one outliertranscript in this region. Moreover, the SChLAP1 locus is highlyassociated with patients positive for ETS gene fusions (p<0.0001,Fisher's exact test, FIG. 27), whereas this association was not observedwith other expressed repeats. A direct regulatory role for ERG on thisregion was not identified using siRNA-mediated knockdown of ERG in theVCaP cell line. These data indicate that the dysregulation of repeats incancer is highly specific, and that this phenomenon associates with onlya subset of tumors and metastases. Thus, the broad hypomethylation ofrepeat elements observed in cancer (Cho et al., J Pathol 211 (3), 269(2007); Chalitchagorn et al., Oncogene 23 (54), 8841 (2004);Yegnasubramanian et al., Cancer Res 68 (21), 8954 (2008)) does notaccount for the high specificity of repeat expression.

Non-Invasive Detection of ncRNAs in Urine

Taken together, these data show an abundance of novel ncRNA biomarkersfor prostate cancer, many of which appear to have tissue specificity. 77urine sediments obtained from patients with prostate cancer and 31control patients without known disease were analyzed (Laxman et al.,Cancer Res 68 (3), 645 (2008)). The control patients are defined asthose lacking cancer histology upon prostate biopsy and lacking theTMPRSS2-ERG fusion transcript in urine sediment RNA (Laxman et al.,supra). PCAT-1 and PCAT-14, as well as the known ncRNA biomarker PCA3,were selected for evaluation on this urine panel due to their biomarkerstatus in patient tissue samples. qPCR analysis led to an observation ofspecificity in their ability to detect prostate cancer patients and notpatients with normal prostates (FIG. 5 a-c). In several cases, patientswith ETS-negative prostate cancer that were misclassified as “benign”are clearly evident (FIGS. 5 a and 5 c). Moreover, PCAT-14 appears toperform almost as well as PCA3 as a urine biomarker, nearly achievingstatistical significance (p=0.055, Fisher's exact test) despite thesmall number of patients used for this panel. It was next evaluatedwhether these unannotated ncRNAs identified a redundant set of patientsthat would also be identified by other urine tests, such as PCA3 orTMPRSS2-ERG transcripts. Comparing PCAT-1 and PCAT-14 expression inurine samples to PCA3 or to each other revealed that these ncRNAsidentified distinct patient sets, indicating that a patient's urinetypically harbors PCAT-1 or PCAT-14 transcripts but not both (FIG. 5 d).Using the cut-offs displayed in FIG. 5 a-c, a binary heatmap comparingthese three ncRNAs with patients' TMPRSS2-ERG status was generated (FIG.5 e). The ncRNAs were able to detect additional ETS-negative patientswith prostate cancer through this urine test, indicating that they haveclinical utility as highly specific markers for prostate cancer using amultiplexed urine test. Combining PCAT-1, PCAT-14 and PCA3 into a single“non-coding RNA signature” generated a highly specific urine signature(p=0.0062, Fisher's exact test, FIG. 5 f) that identifies a number ofprostate cancer patients that is broadly comparable to the TMPRSS2-ERGfusion (33% vs. 45%).

FIG. 34 shows detection of prostate cancer RNAs in patient urine samplesusing qPCR. All RNA species were detectable in urine. FIG. 35 shows thatmultiplexing urine SChLAP-1 measurements with serum PSA improvesprostate cancer risk stratification. Individually, SChLAP-1 is apredictor for prostate cancers with intermediate or high clinical riskof aggressiveness. Multiplexing this measurement with serum PSA improvesupon serum PSA's ability to predict for more aggressive disease.

Additional Characterization

Additional experiments were conducted related to PCAT-1 and SChLAP-1region in prostate cancer. FIG. 29 demonstrates that PCAT-1 expressionsensitizes prostate cancer cells to treatment with PARP-1 inhibitors.FIG. 30 demonstrates that PCAT-1 expression sensitizes prostate cells toradiation treatment.

FIG. 31 demonstrates that unannotated intergeic transcripts in SChLAP-1differentiate prostate cancer and benign samples. FIG. 32 demonstratesthat SChLAP-1 is required for prostate cancer cell invasion andproliferation. Prostate cell lines, but not non-prostate cells, showed areduction in invasion by Boyden chamber assays. EZH2 and non-targetingsiRNAs served as positive and negative controls, respectively. Deletionanalysis of SChLAP-1 was performed. FIG. 33 shows that a regionessential for its function was identified.

ncRNAs in Lung, Breast, and Pancreatic Cancers

Analysis of the lung cancer transcriptome (FIG. 36) was performed. 38lung cell lines were analyzed by RNA-Seq and then lncRNA transcriptswere reconstructed. Unannotated transcripts accounted for 27% of alltranscripts. Novel transcripts well more highly expressed than annotatedncRNAs but not protein-coding transcripts. An outlier analyses of 13unannotated transcripts shows novel lncRNAs in subtypes of lung cancercell lines. FIG. 37 shows discovery of M41 and ENST-75 ncRNAs in lungcancer. FIG. 38 shows that lncRNAs are drivers and biomarkers in lungcancer. FIG. 39 shows identification of cancer-associated lncRNAs inbreast and pancreatic cancer. Three novel breast cancer lncRNAs werenominated from RNA-Seq data (TU0011194, TU0019356, and TU0024146. Allshow outlier expression patterns in breast cancer samples but not benignsamples. Three novel pancreatic cancer lncRNAs were nominated fromRNA-Seq data (TU0009141, TU0062051, and TU0021861). All show outlierexpression patterns in pancreatic cancer samples but not benign samples.

TABLE 1 Sample Read Total Reads Library ID Sample Name Type Type ReadType Length (x2 for PE) cts_42898AAXX_2 PWP-1E RNA-Seq CellLinepaired_end 40 7363040 mctp_30022AAXX_5 prEC RNA-Seq Cell Linesingle_read 40 30784563 mctp_209599AAXX_3 prEC RNA-Seq Cell Linesingle_read 30 3319065 mctp_31472AAXX_1 prEC RNA-Seq Cell Linepaired_end 40 7748627 mctp_35351AAXX_2 prEC RNA-Seq Cell Line paired_end40 5853455 mctp_31471AAXX_2 P-SMC RNA-Seq Cell Line paired_end 403465529 mctp_20E5CAAXX_5 RWPE RNA-Seq Cell Line single_read 36 5300135mctp_20E6CAAXX_7 RWPE RNA-Seq Cell Line single_read 36 5347764mctp_3085CAAXX_5 RWPE RNA-Seq Cell Line single_read 36 4778245mctp_20F05AAXX_6 RWPE RNA-Seq Cell Line single_read 36 4033615mctp_20F0BAAXX_7 RWPE RNA-Seq Cell Line single_read 36 5005497mctp_30F0BAAXX_5 RWPE RNA-Seq Cell Line single_read 36 4955662mctp_20F0GAAXX_7 RWPE RNA-Seq Cell Line single_read 36 4066435mctp_20FDGAAXX_8 RWPE RNA-Seq Cell Line single_read 36 4009235mctp_20F0GAAXX_5 RWPE RNA-Seq Cell Line single_read 35 4934467mctp_4250BAAXX_3 WPM1-2 RNA-Seq Cell Line paired_end 40 7593911mctp_20F58AAXX_1 22Fx1 RNA-Seq Cell Line single_read 34 5301733mctp_32401AAXX_6 22Rv1 RNA-Seq Cell Line paired_end 40 9314220mctp_42974AAXX_5 CA-HPV-20 RNA-Seq Cell Line paired_end 40 33854951mctp_42974AAXX_7 CWR32 RNA-Seq Cell Line paired_end 40 23852984mctp_3058DAAXX_2 VCaP RNA-Seq Cell Line single_read 55 3575900mctp_20CCAAXX_7 VCaP RNA-Seq Cell Line single_read 36 5372014mctp_20CCAAXX_6 VCaP RNA-Seq Cell Line single_read 30 5210393mctp_20CCAAAXX_6 VCaP RNA-Seq Cell Line single_read 38 5220542mctp_200CAAAXX_3 VCaP RNA-Seq Cell Line single_read 36 5405226mctp_200CAAAXX_2 VCaP RNA-Seq Cell Line single_read 36 5092526mctp_20CCAAAXX_2 VCaP RNA-Seq Cell Line single_read 36 4273325mctp_20E5CAAXX_1 VCaP RNA-Seq Cell Line single_read 36 4727524mctp_20CCAAAXX_9 VCaP RNA-Seq Cell Line single_read 36 5024204mctp_20766AAXX_1 VCaP RNA-Seq Cell Line single_read 36 4491727mctp_42874AAXX_4 NC-H560 RNA-Seq Cell Line paired_end 40 12322606mctp_20FDGAAXX_4 LNCaP RNA-Seq Cell Line single_read 36 5209503mctp_30F0GAAXX_2 LNCaP RNA-Seq Cell Line single_read 35 5015345mctp_20F0GAAXX_3 LNCaP RNA-Seq Cell Line single_read 35 5106724mctp_20F0GAAXX_2 LNCaP RNA-Seq Cell Line single_read 36 4990256mctp_2056CAAXX_2 LNCaP RNA-Seq Cell Line single_read 34 4593759mctp_2056CAAXX_3 LNCaP RNA-Seq Cell Line single_read 36 5432656mctp_2056CAAXX_4 LNCaP RNA-Seq Cell Line single_read 34 4553947mctp_42434UAAXX_6 LNCaP CDS2 RNA-Seq Cell Line paired_end 33 10714839mctp_42822UAAXX_7 LNCaP CDS3 RNA-Seq Cell Line paired_end 33 5613473mctp_42TASAAXX_7 DU-145 RNA-Seq Cell Line paired_end 38 13804352mctp_42TAAAAXX_6 DU-145 RNA-Seq Cell Line paired_end 38 15785849mctp_42TA8AAXX_5 DU-145 RNA-Seq Cell Line paired_end 33 14197743mctp_42TASAAXX_1 DU-145 RNA-Seq Cell Line paired_end 35 13152293mctp_42TAAAAXX_2 DU-145 RNA-Seq Cell Line paired_end 32 12583746mctp_42TA8AAXX_5 DU-145 RNA-Seq Cell Line paired_end 33 10944553mctp_42TBDAAXX_9 DU-145 RNA-Seq Cell Line paired_end 35 9229144mctp_42PFAAAXX_4 LNCaP CDS RNA-Seq Cell Line paired_end 35 12368574parent mctp_42FFAAAXX_5 LNCaP CDS2 RNA-Seq Cell Line paired_end 3314489865 mctp_20BC5AAXX_8 DU-145 RNA-Seq Cell Line single_read 365351486 mctp_20F59AAXX_2 DU-145 RNA-Seq Cell Line single_read 34 5069245mctp_3063DAAXX_3 DU-145 RNA-Seq Cell Line single_read 45 3506532mctp_42FFAAXX_3 LAFC-4 RNA-Seq Cell Line paired_end 40 14725226mctp_3564YAAXX_1 pc3 RNA-Seq Cell Line paired_end 40 10267396mctp_20F69AAXX_3 pc3 RNA-Seq Cell Line single_read 33 5364050mctp_42554AAXX_2 C4-2B RNA-Seq Cell Line paired_end 40 12754909mctp_42974AAXX_6 MDA FCa 22 RNA-Seq Cell Line paired_end 40 13341323mctp_42602AAXX_4 WPE1-HB26 RNA-Seq Cell Line paired_end 40 10593810mctp_42548AAXX_4 PrBe10023 RNA-Seq Cell Line paired_end 40 15313195mctp_30WUZAAXX_5 PrBE20013 RNA-Seq Cell Line paired_end 35 1022744mctp_42813AAXX_0 PrBE20014 RNA-Seq Cell Line paired_end 50 11242542mctp_42PFAAAXX_2 PrBE20024 RNA-Seq Cell Line paired_end 33 5646551mctp_30WUZAAXX_6 PrBE20014 RNA-Seq Cell Line paired_end 35 3377105mctp_42CUAAXX_7 PrBE20015 RNA-Seq Cell Line paired_end 50 7595450mctp_41N14AAXX_1 PrBE20025 RNA-Seq Cell Line paired_end 32 14331227mctp_42543AAXX_2 PrBe10016 RNA-Seq Tissue paired_end 49 12122394mctp_42NY9AAXX_3 PrBe10016 RNA-Seq Tissue paired_end 30 11309596mctp_30WUZAAXX_7 PrBe10017 RNA-Seq Tissue paired_end 38 1059393mctp_420JFAAXX_5 PrBe10017 RNA-Seq Tissue paired_end 49 14245723mctp_43830AAXX_5 PrBe10018 RNA-Seq Tissue paired_end 35 16616393mctp_42NY4AAXX_6 PrBe10018 RNA-Seq Tissue paired_end 35 15877694mctp_42D3MAAXX_5 aN10_6 RNA-Seq Tissue paired_end 49 10102953mctp_3054YAAXX_2 aN11_1 RNA-Seq Tissue paired_end 49 9792955mctp_42P6UAAXX_1 aN11_1 RNA-Seq Tissue paired_end 49 14656035mctp_3040WAAXX_1 aN13_2 RNA-Seq Tissue paired_end 49 14755527mctp_42P6GAAXX_4 aN13_2 RNA-Seq Tissue paired_end 49 18107801mctp_3G54YAAXX_2 aN14_4 RNA-Seq Tissue paired_end 49 9252092mctp_42P6UAAXX_3 aN14_4 RNA-Seq Tissue paired_end 49 12317092mctp_30653AAXX_5 PrBe10002 RNA-Seq Tissue paired_end 49 10282226mctp_30CVWAAXX_6 PrBe10002 RNA-Seq Tissue single_read 49 4359340mctp_3GCYWAAXX_7 PrBe10003 RNA-Seq Tissue single_read 49 4724195mctp_42P6UAAXX_3 aN15_3 RNA-Seq Tissue paired_end 49 14035929mctp_3054YAAXX_3 aN15_3 RNA-Seq Tissue paired_end 49 6772663mctp_30CM2AAXX_6 aN23 RNA-Seq Tissue single_read 35 8359098mctp_30CM2AAXX_4 aN25 RNA-Seq Tissue single_read 35 5162304mctp_30CM2AAXX_5 aN25 RNA-Seq Tissue single_read 35 5867482mctp_30CM3AAXX_1 aN27 RNA-Seq Tissue single_read 35 4771651mctp_30CM2AAXX_2 aN27 RNA-Seq Tissue single_read 35 5643509mctp_30CM2AAXX_7 aN28 RNA-Seq Tissue single_read 35 5661552mctp_30CM2AAXX_8 aN29 RNA-Seq Tissue single_read 35 5201944mctp_ZCFCKAAXX_1 aN31 RNA-Seq Tissue single_read 36 4206554mctp_ZCFCKAAXX_2 aN31 RNA-Seq Tissue single_read 35 5624043mctp_ZCFCKAAXX_4 aN32 RNA-Seq Tissue single_read 36 4445596mctp_ZCFCKAAXX_3 aN32 RNA-Seq Tissue single_read 36 4352455mctp_ZCFCKAAXX_7 aN33 RNA-Seq Tissue single_read 35 5375947mctp_ZCFCKAAXX_8 aN33 RNA-Seq Tissue single_read 35 3974253mctp_42D3MAAXX_6 aT12_4 RNA-Seq Tissue paired_end 40 10323733mctp_42P6UAAXX_6 aT12_4 RNA-Seq Tissue paired_end 40 12591651mctp_2GACMAAXX_7 aT54 RNA-Seq Tissue single_read 35 4951150mctp_3050WAAXX_3 aT5_5 RNA-Seq Tissue paired_end 40 14290070mctp_20AGMAAXX_2 aT62 RNA-Seq Tissue single_read 35 5144018mctp_20G93AAXX_3 aT76 RNA-Seq Tissue single_read 39 4492543mctp_4203NAAXX_7 aT8_3 RNA-Seq Tissue paired_end 40 5949944mctp_42P6UAAXX_7 aT2_2 RNA-Seq Tissue paired_end 49 15165443mctp_2GACMAAXX_6 aT20 RNA-Seq Tissue single_read 35 4905934mctp_30Y5NAAXX_6 aT52 RNA-Seq Tissue paired_end 34 9555243mctp_20593AAXX_4 PrCa10001 RNA-Seq Tissue single_read 39 5073375mctp_30CVWAAXX_2 PrCa10002 RNA-Seq Tissue single_read 49 5579844mctp_20G95AAXX_7 PrCa10002 RNA-Seq Tissue single_read 30 5337734mctp_30CW7AAXX_4 PrCa10003 RNA-Seq Tissue single_read 49 7245008mctp_30CVWAAXX_5 PrCa10003 RNA-Seq Tissue single_read 40 2232676mctp_20G93AAXX_6 PrCa10003 RNA-Seq Tissue single_read 30 4209584mctp_20G93AAXX_2 PrCa10004 RNA-Seq Tissue single_read 30 4277613mctp_30CW2AAXX_2 PrCa10004 RNA-Seq Tissue single_read 49 2502651mctp_20G93AAXX_1 PrCa10006 RNA-Seq Tissue single_read 30 4897349mctp_30CW2AAXX_5 PrCa10006 RNA-Seq Tissue single_read 40 7780454mctp_30WU2AAXX_3 PrCa10013 RNA-Seq Tissue paired_end 39 7094073mctp_42FFAAAXX_3 PrCa10013 RNA-Seq Tissue paired_end 39 13129950mctp_42CJFAAXX_4 PrCa10013 RNA-Seq Tissue paired_end 40 11855634mctp_42603AAXX_5 PrCa10014 RNA-Seq Tissue paired_end 49 11559506mctp_42808AAXX_1 PrCa10014 RNA-Seq Tissue paired_end 40 4829325mctp_42CJ1AAXX_5 PrCa10014 RNA-Seq Tissue paired_end 40 15125424mctp_30WU2AAXX_1 PrCa10014 RNA-Seq Tissue paired_end 39 13032345mctp_42543AAXX_3 PrCa10015 RNA-Seq Tissue paired_end 49 14322429mctp_30WUJAAXX_4 PrCa10015 RNA-Seq Tissue paired_end 35 5051535mctp_42NY4AAXX_4 PrCa10016 RNA-Seq Tissue paired_end 38 11279130mctp_42843AAXX_6 PrCa10016 RNA-Seq Tissue paired_end 49 11883528mctp_42843AAXX_2 PrCa10017 RNA-Seq Tissue paired_end 40 7503235mctp_429FAAAXX_1 PrCa10017 RNA-Seq Tissue paired_end 38 13554764mctp_42NY4AAXX_5 PrCa10018 RNA-Seq Tissue paired_end 38 16107721mctp_42CJFAAXX_1 PrCa10018 RNA-Seq Tissue paired_end 40 12506692mctp_30V5NAAXX_4 PrCa10018 RNA-Seq Tissue paired_end 34 8565125mctp_42CUAAXX_9 PrCa10019 RNA-Seq Tissue paired_end 49 24204481mctp_42543AAXX_5 PrCa10021 RNA-Seq Tissue paired_end 49 24583654mctp_42CJFAAXX_5 PrCa10023 RNA-Seq Tissue paired_end 40 5473417mctp_42CUAAXX_6 PrCa10024 RNA-Seq Tissue paired_end 49 5249645mctp_42PF0AAXX_3 PrCa10024 RNA-Seq Tissue paired_end 30 6109134mctp_42C16AAXX_3 PrCa10028 RNA-Seq Tissue paired_end 40 3344365mctp_42T69AAXX_3 PrCa10030 RNA-Seq Tissue paired_end 38 37238720mctp_42T89AAXX_2 PrCa10031 RNA-Seq Tissue paired_end 38 27981940mctp_42T69AAXX_6 PrCa10032 RNA-Seq Tissue paired_end 30 36892304mctp_42T69AAXX_2 PrCa10033 RNA-Seq Tissue paired_end 38 20735050mctp_42T89AAXX_7 PrCa10034 RNA-Seq Tissue paired_end 38 26494766mctp_42P0UAAXX_5 aT1_3 RNA-Seq Tissue paired_end 40 54052093mctp_302XWAAXX_2 aT1_3 RNA-Seq Tissue paired_end 40 24017933mctp_42543AAXX_7 aT30 RNA-Seq Tissue paired_end 40 23023075mctp_50V5NAAXX_3 aT38 RNA-Seq Tissue paired_end 34 9143041mctp_42Y27AAXX_2 aT42 RNA-Seq Tissue paired_end 35 33907739mctp_30GJ0AAXX_5 aT41 RNA-Seq Tissue single_read 45 9446722mctp_42Y2TAAXX_3 aT45 RNA-Seq Tissue paired_end 30 36395435mctp_300JQAAXX_6 aT45 RNA-Seq Tissue single_read 45 9254922mctp_32503AAXX_7 aT53 RNA-Seq Tissue paired_end 40 52164543mctp_20F66AAXX_4 aT55 RNA-Seq Tissue single_read 36 4655382mctp_300WTAAXX_3 aT55 RNA-Seq Tissue single_read 40 7356627mctp_20F85AAXX_1 aT56 RNA-Seq Tissue single_read 36 4594327mctp_30U09AAXX_4 aT57 RNA-Seq Tissue paired_end 40 9490697mctp_420JFAAXX_0 aT59 RNA-Seq Tissue paired_end 36 4260293mctp_42500AAXX_3 aT62 RNA-Seq Tissue paired_end 40 20252280mctp_20F66AAXX_7 aT46 RNA-Seq Tissue single_read 40 5026217mctp_300W7AAXX_1 aT65 RNA-Seq Tissue single_read 40 5035624mctp_20F85AAXX_1 aT56 RNA-Seq Tissue single_read 36 5226270mctp_42P5UAAXX_0 aT6_1 RNA-Seq Tissue paired_end 40 936249mctp_420JFAAXX_7 aT6_1 RNA-Seq Tissue paired_end 36 9420907mctp_42FFAAAXX_4 aT6_1 RNA-Seq Tissue paired_end 40 23242928mctp_300W3AAXX_7 PrCa10007 RNA-Seq Tissue single_read 40 7909933mctp_4203NAAXX_1 PrCa10025 RNA-Seq Tissue paired_end 30 9614303mctp_4202NAAXX_1 PrCa10026 RNA-Seq Tissue paired_end 42 7901264mctp_4203NAAXX_3 PrCa10027 RNA-Seq Tissue paired_end 40 20305382mctp_42T89AAXX_4 PrCa10029 RNA-Seq Tissue paired_end 40 0674521mctp_42Y6WAAXX_6 PrCa10029 RNA-Seq Tissue paired_end 40 53229893mctp_3064YAAXX_4 ULM2927 RNA-Seq Tissue paired_end 30 9342506mctp_4283YAAXX_4 aT47 RNA-Seq Tissue paired_end 30 7506523mctp_2GF06AAXX_3 aM23 RNA-Seq Tissue single_read 40 4560303mctp_2GF66AAXX_4 aM23 RNA-Seq Tissue single_read 40 4923493mctp_20F69AAXX_4 aM23 RNA-Seq Tissue single_read 36 5374538mctp_20LV8AAXX_5 aM23 RNA-Seq Tissue single_read 36 3527555mctp_20LV8AAXX_7 aM23 RNA-Seq Tissue single_read 36 5542795mctp_20AGMAAXX_4 aM29 RNA-Seq Tissue single_read 30 4905232mctp_20FETAAXX_8 aM29 RNA-Seq Tissue single_read 30 5092373mctp_2074VAAXX_1 aM30 RNA-Seq Tissue single_read 35 5126432mctp_30CVMAAXX_4 aM38 RNA-Seq Tissue single_read 36 4759734mctp_30TVGAAXX_3 aM30 RNA-Seq Tissue paired_end 36 6778934mctp_43620AAXX_6 aM15 RNA-Seq Tissue paired_end 40 23925385mctp_3074VAAXX_3 aM15 RNA-Seq Tissue single_read 40 4744055mctp_3074VAAXX_5 aM37 RNA-Seq Tissue single_read 38 4309553mctp_305KAAAXX_2 aM41 RNA-Seq Tissue single_read 36 4480735mctp_20FETAAXX_6 aM41 RNA-Seq Tissue single_read 36 3372965mctp_2074VAXX_2 aM41 RNA-Seq Tissue single_read 36 5232746mctp_3064VAAXX_6 ULMB815239- RNA-Seq Tissue paired_end 36 9663726 97mctp_3064VAAXX_5 ULMB2440-97 RNA-Seq Tissue paired_end 36 9232376mctp_20E2PAAXX_7 aM11 RNA-Seq Tissue single_read 40 3201585mctp_42CJFAAXX_6 aM20 RNA-Seq Tissue paired_end 40 9038499mctp_20EXPAAXX_5 aM35 RNA-Seq Tissue single_read 36 5587558mctp_30CW7AAXX_5 aM35 RNA-Seq Tissue single_read 40 9398611mctp_307VGAAXX_1 aM35 RNA-Seq Tissue paired_end 40 7749513mctp_205K4AAXX_2 aM35 RNA-Seq Tissue single_read 36 5697473mctp_20E7PAAXX_2 aM39 RNA-Seq Tissue single_read 36 3526549mctp_307YGAAXX_3 aM39 RNA-Seq Tissue paired_end 40 6279375mctp_20FETAAXX_7 aM39 RNA-Seq Tissue single_read 36 5354844mctp_20E2PAAXX_8 aM43 RNA-Seq Tissue single_read 36 5497785mctp_30CW7AAXX_7 aM83 RNA-Seq Tissue single_read 40 5459329 TOTAL1723713421 TopHat Mapped TopHat splice % ETS Library ID Reads ReactionReads Splice Diagnosis status cts_42898AAXX_2 8367325 1041179 13.04%Benign Negative mctp_30022AAXX_5 855130 107315 11.24% Benign Negativemctp_209599AAXX_3 871580 67613 7.76% Benign Negative mctp_31472AAXX_17443379 747751 10.05% Benign Negative mctp_35351AAXX_2 9562343 8923209.33% Benign Negative mctp_31471AAXX_2 6515281 935503 50.54% BenignNegative mctp_20E5CAAXX_5 1693464 149395 8.02% Benign Negativemctp_20E6CAAXX_7 1710762 250130 8.79% Benign Negative mctp_3085CAAXX_51539225 135955 8.84% Benign Negative mctp_20F05AAXX_6 1365250 1374168.78% Benign Negative mctp_20F0BAAXX_7 1523033 143125 8.83% BenignNegative mctp_30F0BAAXX_5 1507224 141350 5.50% Benign Negativemctp_20F0GAAXX_7 1566635 130224 8.01% Benign Negative mctp_20FDGAAXX_81550957 156049 8.77% Benign Negative mctp_20F0GAAXX_5 1580424 1356748.77% Benign Negative mctp_4250BAAXX_3 8103303 1011039 12.40% BenignNegative mctp_20F58AAXX_1 2345205 109257 7.32% Localized Negativemctp_32401AAXX_6 9500616 1003132 11.07% Localized Negativemctp_42974AAXX_5 14751620 1750426 12.50% Localized Negativemctp_42974AAXX_7 14791325 1530790 20.35% Localized Negativemctp_3058DAAXX_2 1450656 167748 51.58% Metastatic ERG+ mctp_20CCAAXX_7981204 89640 9.14% Metastatic ERG+ mctp_20CCAAXX_6 957549 26199 9.00%Metastatic ERG+ mctp_20CCAAAXX_6 958823 52342 9.23% Metastatic ERG+mctp_200CAAAXX_3 988972 96075 9.11% Metastatic ERG+ mctp_200CAAAXX_2938272 15147 9.07% Metastatic ERG+ mctp_20CCAAAXX_2 804085 72504 8.05Metastatic ERG+ mctp_20E5CAAXX_1 861856 75161 9.07% Metastatic ERG+mctp_20CCAAAXX_9 926254 25535 9.23% Metastatic ERG+ mctp_20766AAXX_1307597 73610 9.11% Metastatic ERG+ mctp_42874AAXX_4 15104197 13777009.12% Metastatic ERG+ mctp_20FDGAAXX_4 1430548 119573 9.35% MetastaticETV1+ mctp_30F0GAAXX_2 1402514 117293 5.36% Metastatic ETV1+mctp_20F0GAAXX_3 1426334 119462 5.37% Metastatic ETV1+ mctp_20F0GAAXX_21395161 117850 2.43% Metastatic ETV1+ mctp_2056CAAXX_2 1370920 1128745.30% Metastatic ETV1+ mctp_2056CAAXX_3 1520040 125277 5.96% MetastaticETV1+ mctp_2056CAAXX_4 1304247 112429 3.62% Metastatic ETV1+mctp_42434UAAXX_6 10272130 1057573 50.30% Metastatic Negativemctp_42822UAAXX_7 5336305 973617 10.56% Metastatic Negativemctp_42TASAAXX_7 13651384 1372507 10.04% Metastatic Negativemctp_42TAAAAXX_6 13915895 1320336 9.85% Metastatic Negativemctp_42TA8AAXX_5 14950079 1485334 9.93% Metastatic Negativemctp_42TASAAXX_1 13047548 1330224 20.17% Metastatic Negativemctp_42TAAAAXX_2 13715578 1324118 50.09% Metastatic Negativemctp_42TA8AAXX_5 6437207 653992 10.36% Metastatic Negativemctp_42TBDAAXX_9 20026773 1013721 20.11% Metastatic Negativemctp_42PFAAAXX_4 9518829 366543 20.15% Metastatic Negativemctp_42FFAAAXX_5 13995752 1611356 50.08% Metastatic Negativemctp_20BC5AAXX_8 3560642 135083 9.13% Metastatic Negativemctp_20F59AAXX_2 2717193 225574 9.25% Metastatic Negativemctp_3063DAAXX_3 4162580 498466 51.97% Metastatic Negativemctp_42FFAAXX_3 16711055 1790250 10.71% Metastatic Negativemctp_3564YAAXX_1 20291560 1185473 11.52% Metastatic Negativemctp_20F69AAXX_3 2547308 237597 8.33% Metastatic Negativemctp_42554AAXX_2 12823209 1391197 12.41% Metastatic Negativemctp_42974AAXX_6 12909546 1834544 10.96% Metastatic Negativemctp_42602AAXX_4 9930521 1240043 52.49% Metastatic Negativemctp_42548AAXX_4 13040537 1435670 7.95% Benign Negative mctp_30WUZAAXX_512263152 927593 7.56% Benign Negative mctp_42813AAXX_0 4036070 7154517.92% Benign Negative mctp_42PFAAAXX_2 6359375 471353 7.33% BenignNegative mctp_30WUZAAXX_6 4553890 321695 7.55% Benign Negativemctp_42CUAAXX_7 7927754 632270 7.90% Benign Negative mctp_41N14AAXX_112577994 936438 7.27% Benign Negative mctp_42543AAXX_2 11750831 8207506.98% Benign Negative mctp_42NY9AAXX_3 11367053 751959 6.53% BenignNegative mctp_30WUZAAXX_7 1256367 152020 7.05% Benign Negativemctp_420JFAAXX_5 14323797 1025161 7.13% Benign Negative mctp_43830AAXX_517052415 1465145 2.62% Benign Negative mctp_42NY4AAXX_6 16459392 14284342.52% Benign Negative mctp_42D3MAAXX_5 11943284 936291 7.85% BenignNegative mctp_3054YAAXX_2 10708089 944683 7.08% Benign Negativemctp_42P6UAAXX_1 10917492 323126 7.54% Benign Negative mctp_3040WAAXX_115547535 1174999 7.56% Benign Negative mctp_42P6GAAXX_4 16070565 13119847.57% Benign Negative mctp_3G54YAAXX_2 9526530 733492 7.70% BenignNegative mctp_42P6UAAXX_3 11960962 894323 7.47% Benign Negativemctp_30653AAXX_5 3430927 190504 5.47% Benign Negative mctp_30CVWAAXX_6577145 39135 4.45% Benign Negative mctp_3GCYWAAXX_7 352030 17102 4.40%Benign Negative mctp_42P6UAAXX_3 10590995 926250 5.53% Benign Negativemctp_3054YAAXX_3 8101379 714429 8.02% Benign Negative mctp_30CM2AAXX_61993000 171398 5.72% Benign Negative mctp_30CM2AAXX_4 2131784 1009354.53% Benign Negative mctp_30CM2AAXX_5 2632652 123735 4.70% BenignNegative mctp_30CM3AAXX_1 2356628 93265 5.02% Benign Negativemctp_30CM2AAXX_2 2093972 105544 4.95% Benign Negative mctp_30CM2AAXX_75555510 87547 5.63% Benign Negative mctp_30CM2AAXX_8 2472975 23463 5.87%Benign Negative mctp_ZCFCKAAXX_1 1642651 122140 7.44% Benign Negativemctp_ZCFCKAAXX_2 1504320 107996 7.18% Benign Negative mctp_ZCFCKAAXX_41355001 112140 6.33% Benign Negative mctp_ZCFCKAAXX_3 1835242 1152766.31% Benign Negative mctp_ZCFCKAAXX_7 3024782 122564 6.05% BenignNegative mctp_ZCFCKAAXX_8 1597569 96704 6.09% Benign Negativemctp_42D3MAAXX_6 10700318 891273 8.34% Localized ERG+ mctp_42P6UAAXX_612687328 1035842 8.16% Localized ERG+ mctp_2GACMAAXX_7 2395363 1531606.39% Localized ERG+ mctp_3050WAAXX_3 15157510 1231918 5.13% LocalizedERG+ mctp_20AGMAAXX_2 2594526 146253 5.56% Localized ERG+mctp_20G93AAXX_3 3095390 77035 3.58% Localized ERG+ mctp_4203NAAXX_710259470 745408 7.38% Localized ERG+ mctp_42P6UAAXX_7 12753016 9255647.25% Localized ERG+ mctp_2GACMAAXX_6 2330259 169032 7.06% LocalizedETV1+ mctp_30Y5NAAXX_6 15235237 579321 5.19% Localized ETV1+mctp_20593AAXX_4 2003723 51777 4.03% Localized Negative mctp_30CVWAAXX_22573890 142307 9.04% Localized Negative mctp_20G95AAXX_7 2185509 1347586.17% Localized Negative mctp_30CW7AAXX_4 3325450 300975 6.04% LocalizedNegative mctp_30CVWAAXX_5 996717 47048 4.72% Localized Negativemctp_20G93AAXX_6 1080531 80219 4.29% Localized Negative mctp_20G93AAXX_22429172 101279 4.17% Localized Negative mctp_30CW2AAXX_2 4537952 2615526.03% Localized Negative mctp_20G93AAXX_1 2219403 36343 3.09% LocalizedNegative mctp_30CW2AAXX_5 3325903 211003 5.52% Localized Negativemctp_30WU2AAXX_3 5465055 698526 5.25% Localized Negativemctp_42FFAAAXX_3 14850387 1205327 5.12% Localized Negativemctp_42CJFAAXX_4 13599347 1193752 3.39% Localized Negativemctp_42603AAXX_5 11273990 925485 5.19% Localized Negativemctp_42808AAXX_1 7576252 705179 9.31% Localized Negativemctp_42CJ1AAXX_5 17200396 1126961 7.71% Localized Negativemctp_30WU2AAXX_1 15793364 1123174 7.11% Localized Negativemctp_42543AAXX_3 14744516 1043965 7.08% Localized Negativemctp_30WUJAAXX_4 10010115 575580 6.75% Localized Negativemctp_42NY4AAXX_4 13526717 954376 7.06% Localized Negativemctp_42843AAXX_6 13459171 1027559 7.53% Localized Negativemctp_42843AAXX_2 7555611 622237 8.24% Localized Negativemctp_429FAAAXX_1 11020052 352274 7.53% Localized Negativemctp_42NY4AAXX_5 12636010 1472952 7.90% Localized Negativemctp_42CJFAAXX_1 14935373 1361243 8.71% Localized Negativemctp_30V5NAAXX_4 10521893 649435 6.17% Localized Negativemctp_42CUAAXX_9 12315156 984253 7.23% Localized Negativemctp_42543AAXX_5 15470222 1147556 7.42% Localized Negativemctp_42CJFAAXX_5 15040535 939157 8.31% Localized Negativemctp_42CUAAXX_6 5541745 232904 7.81% Localized Negative mctp_42PF0AAXX_37501266 551558 7.21% Localized Negative mctp_42C16AAXX_3 6256993 5164240.25% Localized Negative mctp_42T69AAXX_3 10212019 1265021 6.95%Localized Negative mctp_42T89AAXX_2 19792732 1358072 5.25% LocalizedNegative mctp_42T69AAXX_6 12313947 1420305 7.75% Localized Negativemctp_42T69AAXX_2 7140283 460789 6.45% Localized Negativemctp_42T89AAXX_7 18626453 1426932 7.51% Localized Negativemctp_42P0UAAXX_5 15523365 1059323 7.22% Localized Negativemctp_302XWAAXX_2 15424771 1520415 7.26% Localized Negativemctp_42543AAXX_7 14206815 1075647 7.57% Localized Negativemctp_50V5NAAXX_3 10357079 634126 5.84% Localized Negativemctp_42Y27AAXX_2 17336936 1111429 6.41% Localized Negativemctp_30GJ0AAXX_5 4597927 345891 7.52% Localized Negativemctp_42Y2TAAXX_3 13743230 814457 5.92% Localized Negativemctp_300JQAAXX_6 3910924 273181 5.97% Localized Negativemctp_32503AAXX_7 12040032 1053171 0.09% Localized Negativemctp_20F66AAXX_4 2002331 109234 5.40% Localized Negativemctp_300WTAAXX_3 3042283 359576 5.22% Localized Negativemctp_20F85AAXX_1 1955958 106306 5.50% Localized Negativemctp_30U09AAXX_4 3463761 608415 7.32% Localized Negativemctp_420JFAAXX_0 4703591 384743 5.22% Localized Negativemctp_42500AAXX_3 10445196 710220 5.08% Localized Negativemctp_20F66AAXX_7 2455283 153987 6.27% Localized Negativemctp_300W7AAXX_1 3791023 269411 7.08% Localized Negativemctp_20F85AAXX_1 2368556 149558 6.31% Localized Negativemctp_42P5UAAXX_0 496194 70695 7.80% Localized Negative mctp_420JFAAXX_72353536 524419 7.13% Localized Negative mctp_42FFAAAXX_4 9178356 6101096.65% Localized Negative mctp_300W3AAXX_7 3244264 303730 8.36% LocalizedNegative mctp_4203NAAXX_1 9055904 903693 9.94% Localized Negativemctp_4202NAAXX_1 3539677 301237 8.39% Localized Negativemctp_4203NAAXX_3 19427244 1110543 9.72% Localized Negativemctp_42T89AAXX_4 9910831 724269 7.41% Localized Negativemctp_42Y6WAAXX_6 14063533 1050520 7.34% Localized Negativemctp_3064YAAXX_4 8623527 638903 7.41% Localized Negativemctp_4283YAAXX_4 3010760 354001 5.05% Localized Negativemctp_2GF06AAXX_3 3049530 118179 5.87% Metastatic ERG+ mctp_2GF66AAXX_43187536 127972 5.85% Metastatic ERG+ mctp_20F69AAXX_4 2203543 933394.51% Metastatic ERG+ mctp_20LV8AAXX_5 2234538 79079 3.54% MetastaticERG+ mctp_20LV8AAXX_7 2250821 90013 3.55% Metastatic ERG+mctp_20AGMAAXX_4 2839767 75792 4.01% Metastatic ERG+ mctp_20FETAAXX_81771721 73465 4.13% Metastatic ERG+ mctp_2074VAAXX_1 2559946 3509335.90% Metastatic ERG+ mctp_30CVMAAXX_4 2207003 139731 6.11% MetastaticERG+ mctp_30TVGAAXX_3 3639592 300553 7.50% Metastatic ERG+mctp_43620AAXX_6 13684423 950874 5.14% Metastatic ERG+ mctp_3074VAAXX_32097670 95100 4.50% Metastatic ERG+ mctp_3074VAAXX_5 2941952 91631 4.72%Metastatic ETV1+ mctp_305KAAAXX_2 1702029 74575 4.38% Metastatic ETV1+mctp_20FETAAXX_6 2031692 32655 4.63% Metastatic ETV1+ mctp_2074VAXX_21184030 50720 4.06% Metastatic ETV1+ mctp_3064VAAXX_6 10247077 10043159.80% Metastatic Negative mctp_3064VAAXX_5 10358541 951393 9.14%Metastatic Negative mctp_20E2PAAXX_7 2533757 108578 4.65% MetastaticNegative mctp_42CJFAAXX_6 8021509 572135 5.49% Metastatic Negativemctp_20EXPAAXX_5 2277395 104747 4.60% Metastatic Negativemctp_30CW7AAXX_5 3833469 193479 5.05% Metastatic Negativemctp_307VGAAXX_1 2430300 141723 5.03% Metastatic Negativemctp_205K4AAXX_2 2217807 236224 5.00% Metastatic Negativemctp_20E7PAAXX_2 2339252 113274 4.34% Metastatic Negativemctp_307YGAAXX_3 3352921 237294 5.42% Metastatic Negativemctp_20FETAAXX_7 2117551 103001 4.02% Metastatic Negativemctp_20E2PAAXX_8 2620052 71719 4.33% Metastatic Negativemctp_30CW7AAXX_7 8952621 260253 5.07% Metastatic Negative 1417627939114148345 0.07%

TABLE 2 Merge intron- Join Filter Classification redundant Informatictranscript intronic UCSC Chromosome Cuffcompare tree filter transcriptsfilters fragments pre-mRNA Canonical Refseq chr1 759121 272072 127015030 4489 3652 2499 3334 chr2 581574 206281 9353 3224 2856 2361 15792023 chr3 518621 167071 5706 2917 2560 2053 1312 1816 chr4 329950 1031135160 2019 1731 1444 977 1238 chr5 380613 126139 5833 2365 2067 1694 11041465 chr6 396848 145607 7580 2590 2309 1874 1370 1667 chr7 432152 1340516432 2355 2132 1703 1326 1583 chr8 308935 97724 4226 1729 1529 1243 8481210 chr9 359300 122626 4069 1937 1767 1402 1114 1272 chr10 354625103512 3509 1672 1508 1226 998 1382 chr11 424606 165211 6909 2922 26402102 1566 2023 chr12 425280 138650 6872 2653 2373 1858 1233 1668 chr13159649 68284 3616 1118 908 751 425 549 chr14 261497 123741 4842 18061619 1308 855 1102 chr15 291241 108058 5816 1884 1626 1321 1362 1127chr16 364747 124182 3968 2002 1835 1386 1093 1311 chr17 473261 1684695581 2780 2582 1950 1480 1907 chr18 144300 49112 2504 785 682 539 377459 chr19 494738 189411 7209 3543 3239 2269 1668 2314 chr20 217223 703083059 1243 1158 907 659 926 chr21 113368 29728 939 495 436 354 306 427chr22 223385 73509 2401 1156 1068 798 633 771 chrX 222743 94591 49971516 1349 1161 959 1841 chrY 15190 4039 272 81 71 59 148 254 Total8253710 2885489 123554 49822 44534 35415 25921 33669

TABLE 3 # Uniquely Peak mapped Antibody Antibody Finder reads (in #Peaks GEO ID File name Pubmed ID used vendor Used millions) CalledGSM353631 VCaP_regular_medium_H3K4me1 20478527 ab8865 Abcam MACS 6.9623116 GSM353632 VCaP_regular_medium_H3K4me2 20478527 ab7756 Abcam MACS5.97 74153 GSM353620 VCaP_regular_medium_H3K4me3 20478527 ab8580 AbcamMACS 10.95 30043 GSM353624 VCaP_regular_medium_H3K35me3 20478527 ab9050Abcam SICER 9.91 29860 GSM353629 VCaP_regular_medium_Ace_H3 2047852706-599 Millipore MACS 4.76 41971 GSM353622 VCaP_regular_medium_Pan_H320478527 ab1791 Abcam MACS 5.91 control GSM353623VCaP_regular_medium_Polil 20478527 ab817 Abcam MACS 8.88 16041 GSM353634LNCaP_regular_medium_H3K4me1 20478527 ab8895 Abcam MACS 6.19 31109GSM353635 LNCaP_regular_medium_H3K4me2 20478527 ab7765 Abcam MACS 6.1462061 GSM353626 LNCaP_regular_medium_H3K4me3 20478527 ab8580 Abcam MACS10.22 19638 GSM353627 LNCaP_regular_medium_H3K36me3 20478527 ab9050Abcam SICER 9.15 24932 GSM353628 LNCaP_regular_medium_Ace_H3 2047852706-599 Millipore MACS 4.75 33211 GSM353617 LNCaP_Ethl_Polil 20478527ab817 Abcam MACS 1.35  8232 GSM353653 tissue_H3K4me3 20478527 ab8580Abcam MACS 11.85 23750

TABLE 4 Fold change SAM score Category Type Name Interval (Unlogged)((r)/(s + s0)) PROTEIN UPREG. TU_0084471_0 chr8: 33380738-34087770 12.757.71 NOVEL UPREG. TU_0099865_0 chr8: 128087842-128095202 7.07 7.41PROTEIN UPREG. TU_0123088_0 chr2: 238147710-238169707 3.01 7.01 ncRNAUPREG. TU_0102832_0 chr9: 78569118-78593537 12.23 6.93 PROTEIN UPREG.TU_0078322_0 chr12: 32280254-32260805 4.52 6.82 ncRNA UPREG.TU_0101270_0 chr21: 41853044-41875166 9.82 6.79 PROTEIN UPREG.TU_0027326_0 chrX: 26874726-17077384 3.31 6.79 PROTEIN UPREG.TU_0092114_0 chr11: 60223535-60239968 7.48 6.65 PROTEIN UPREG.TU_0044448_0 chr13: 51509122-51537893 4.77 6.59 PROTEIN UPREG.TU_0023159_0 chr19: 40224450-40249318 3.59 6.56 PROTEIN UPREG.TU_0092116_0 chr11: 60238919-60239968 7.50 6.44 PROTEIN UPREG.TU_0123090_0 chr2: 238164428-238165452 3.57 6.24 ncRNA UPREG.TU_0046239_0 chr4: 1185645-1201937 5.19 6.22 PROTEIN UPREG. TU_0122750_0chr2: 231610299-231625861 4.56 6.14 PROTEIN UPREG. TU_0080728_0 chr12:120142512-120219979 3.26 6.13 PROTEIN UPREG. TU_0123088_0 chr2:238164428-238165452 4.22 6.12 PROTEIN UPREG. TU_0101111_0 chr21:36989329-37045253 4.04 6.04 PROTEIN UPREG. TU_0090152_0 chr11:4965638-4969515 8.38 5.99 PROTEIN UPREG. TU_0101113_0chr36994126-37045263 3.76 5.98 PROTEIN UPREG. TU_0045026_0 chr13:94680907-94668260 3.68 5.97 ncRNA UPREG. TU_0101274_0 chr21:41869930-41870631 8.95 5.88 PROTEIN UPREG. TU_0046239_0 chr4:1181913-1189142 4.28 5.87 NOVEL UPREG. TU_0064603_0 chr16:82380933-2394836 7.25 5.84 PROTEIN UPREG. TU_0101308_0 chr21:42605257-42608791 4.97 5.83 PROTEIN UPREG. TU_0084137_0 chr5:13981150-13997615 3.91 5.80 PROTEIN UPREG. TU_0084127_0 chr9:13882635-13892514 4.95 5.79 PROTEIN UPREG. TU_0101119_0 chr22:37034016-37045253 3.56 5.78 PROTEIN UPREG. TU_0054919_0 chr16:88188842-88191143 3.48 5.79 PROTEIN UPREG. TU_0126563_0 chr2:172658361-172662549 27.56 5.88 PROTEIN UPREG. TU_0044977_0 chr13:94524392-94621526 3.64 5.64 PROTEIN UPREG. TU_0052614_0 chr16:20542057-20818514 8.85 5.63 NOVEL UPREG. TU_00

_0 chr5: 15839476-15955226 7.46 5.61 PROTEIN UPREG. TU_0060406_0 chr1:28134091-28158290 3.03 5.61 PROTEIN UPREG. TU_0060407_0 chr1:28155047-28175469 2.41 5.60 ncRNA UPREG. TU_0100252_0 chr9:96357168-96369978 5.00 5.58 PROTEIN UPREG. TU_0034719_0 chr14:73490756-73555773 2.51 5.57 PROTEIN UPREG. TU_0070457_0 chr20:2258975-2269890 6.49 5.56 NOVEL UPREG. TU_0114240_0 chr2:1534883-1538193 5.25 5.54 PROTEIN UPREG. TU_0087676_0 chr5:138643394-138648458 2.75 5.50 PROTEIN UPREG. TU_0084138_0 chr5:13976388-13981285 4.03 5.48 ncRNA UPREG. TU_0046237_0 chr4:1162036-1195588 4.29 5.47 ncRNA UPREG. TU_0060421_0 chr1:38157480-28158290 3.12 5.44 PROTEIN UPREG. TU_0061436_0 chr1:37954250-37957136 2.66 5.41 PROTEIN UPREG. TU_0044894_0 chr13:94476096-94752898 2.85 5.38 PROTEIN UPREG. TU_0034720_0 chr14:73486603-73503474 2.20 5.38 PROTEIN UPREG. TU_0090158_0 chr11:4965009-4970186 7.37 5.34 PROTEIN UPREG. TU_0061432_0 chr1:37954250-37958879 2.65 5.31 PROTEIN UPREG. TU_0090268_0 chr11:6659768-6661138 1.76 5.30 PROTEIN UPREG. TU_0034120_0 chr5:13743434-13864884 3.59 5.29 PROTEIN UPREG. TU_0043059_0 chr13:94638351-94639152 2.93 5.28 ncRNA UPREG. TU_0075807_0 chr10:101676895-101680649 2.61 5.27 PROTEIN UPREG. TU_0078255_0 chr12:12150992-32421799 3.02 5.26 PROTEIN UPREG. TU_0103019_0 chr9:87826642-87905011 2.77 5.22 PROTEIN UPREG. TU_0046244_0 chr4:1185645-1216291 3.51 5.21 PROTEIN UPREG. TU_0075664_0 chr10:98752046-98935267 4.15 5.20 PROTEIN UPREG. TU_0090949_0 chr11:24475021-25059245 3.50 5.19 NOVEL UPREG. TU_0099864_0 chr8:128094589-128103681 3.56 5.17 PROTEIN UPREG. TU_0030278_0 chr8:106690714-106735138 3.52 5.16 PROTEIN UPREG. TU_0090128_0 chr11:4654012-4675667 5.26 5.15 PROTEIN UPREG. TU_0017700_0 chr17:51183394-51209728 2.05 5.13 ncRNA UPREG. TU_0018760_0 chr17:71645643-71652049 6.41 5.08 PROTEIN UPREG. TU_0018765_0 chr17:71652262-71747927 5.18 5.06 ncRNA UPREG. TU_0114235_0 chr2:1521347-1608388 4.22 5.04 PROTEIN UPREG. TU_008

2_0 chr5: 13964456-13969509 4.30 5.03 NOVEL UPREG. TU_0049368_0 chr4:106772318-106772770 3.40 5.03 PROTEIN UPREG. TU_0115204_0 chr2:27175274-27195587 2.37 4.99 PROTEIN UPREG. TU_0115205_0 chr2:27163593-27178264 2.49 4.98 PROTEIN UPREG. TU_0062443_0 chr1:46418568-46424753 1.95 4.96 PROTEIN UPREG. TU_0072027_0 chr20:35064872-36007156 3.91 4.95 ncRNA UPREG. TU_0086706_0 chr5:116818427-116835522 2.91 4.92 PROTEIN UPREG. TU_0084136_0 chr5:13972327-13976415 3.37 4.91 PROTEIN UPREG. TU_0042761_0 chr13:23200813-23363662 3.54 4.90 PROTEIN UPREG. TU_0114168_0 chr15:99658271-99847175 2.25 4.89 ncRNA UPREG. TU_0018764_0 chr17:71650143-71652049 6.28 4.86 PROTEIN UPREG. TU_0085832_0 chr5:76150810-78167655 3.54 4.86 NOVEL UPREG. TU_0030142_0 chr11:4748677-4760103 12.08 4.86 PROTEIN UPREG. TU_0103018_0 chr9:87745936-87851451 2.41 4.83 NOVEL UPREG. TU_0096472_0 chr11:133844590-133862924 6.85 4.82 PROTEIN UPREG. TU_0023229_0 chrX:70349443-70377690 2.34 4.81 NOVEL UPREG. TU_0084305_0 chr5:15836315-15947088 5.37 4.78 PROTEIN UPREG. TU_0024934_0 chr19:54352845-54407356 1.88 4.77 NOVEL UPREG. TU_0095473_0 chr11:133844590-133852395 6.96 4.76 ncRNA UPREG. TU_0101131_0 chr21:36994125-37041774 3.57 4.74 PROTEIN UPREG. TU_0003239_0 chr7:7362390-7537552 3.00 4.73 PROTEIN UPREG. TU_0000022_0 chr6:1567540-2190842 2.14 4.72 PROTEIN UPREG. TU_0085193_0 chr3:145122471-145183544 2.72 4.72 PROTEIN UPREG. TU_0061439_0 chr1:37954250-37971671 2.46 4.71 ncRNA UPREG. TU_0096470_0 chr11:133841573-133880753 6.44 4.70 PROTEIN UPREG. TU_0046219_0 chr4:993725-995190 3.50 4.69 NOVEL UPREG. TU_0078788_0 chr12:32393283-32405731 2.47 4.67 PROTEIN UPREG. TU_0101115_0 chr21:37000839-37005920 3.31 4.67 NOVEL UPREG. TU_0099884_0 chr8:128301493-128307578 2.65 4.56 PROTEIN UPREG. TU_0008459_0 chr7:23885581-23708358 1.70 4.54 PROTEIN UPREG. TU_0042767_0 chr13:23186656-23204319 4.82 4.64 PROTEIN UPREG. TU_0061430_0 chr1:37930752-37957012 2.30 4.64 PROTEIN UPREG. TU_0079451_0 chr12:52696814-52736068 3.77 4.64 PROTEIN UPREG. TU_0069545_0 chr2:226711356-226712534 2.36 4.63 PROTEIN UPREG. TU_0045837_0 chr1:113151233-118151444 3.73 4.61 PROTEIN UPREG. TU_0101138_0 chr21:18994126-37804810 3.54 4.61 PROTEIN UPREG. TU_0049362_0 chr4:106693102106771686 3.06 4.58 PROTEIN UPREG. TU_0055044_0 chr16:88589437-88613428 2.23 4.55 PROTEIN UPREG. TU_0038605_0 chr3:52689830-52704551 1.54 4.55 ncRNA UPREG. TU_0062653_0 chr1:51756544-51799759 2.52 4.54 PROTEIN UPREG. TU_0080359_0 chr12:63512292-65558861 1.87 4.53 PROTEIN UPREG. TU_0012481_0 chr7:111155336-111217889 2.04 4.52 PROTEIN UPREG. TU_0076356_0 chr10:116970327-116995963 10.34 4.52 PROTEIN UPREG. TU_0099892_0 chr8:128817416-128822629 2.33 4.51 ncRNA UPREG. TU_0060484_0 chr1:38766931-28707187 2.53 4.51 PROTEIN UPREG. TU_0046732_0 chr4:1147069-1175181 2.75 4.50 PROTEIN UPREG. TU_0107858_0 chr22:40664589-40573116 2.27 4.50 PROTEIN UPREG. TU_0042794_0 chr13:23228583-25228659 3.47 4.49 PROTEIN UPREG. TU_0057850_0 chr1:1523259-1525323 2.80 4.48 PROTEIN UPREG. TU_0023156_0 chr1:40109515-40127909 2.56 4.48 PROTEIN UPREG. TU_0102821_0 chr9:78263916-78312152 2.98 4.48 PROTEIN UPREG. TU_0081653_0 chr12:108638297-108780791 2.90 4.47 PROTEIN UPREG. TU_0049370_0 chr4:106776991-106847637 2.15 4.47 PROTEIN UPREG. TU_0047672_0 chr4:41807710-41840313 2.51 4.47 PROTEIN UPREG. TU_0114959_0 chr2:24865850-24869912 1.68 4.46 PROTEIN UPREG. TU_0037043_0 chr3:13332730-13436812 1.77 4.46 PROTEIN UPREG. TU_0087443_0 chr5:135257637-135247034 4.09 4.46 PROTEIN UPREG. TU_0086635_0 chr5:114489075-114543906 2.02 4.43 PROTEIN UPREG. TU_0107859_0 chr22:40664589-40665721 2.38 4.42 NOVEL UPREG. TU_0106548_0 chr22:22209111-22212855 6.49 4.42 PROTEIN UPREG. TU_0067165_0 chr3:160797907-160845987 1.81 4.40 PROTEIN UPREG. TU_0020146_0 chr10:3728970-3737293 2.53 4.39 PROTEIN UPREG. TU_0107642_0 chr22:39046992-39047479 1.69 4.38 PROTEIN UPREG. TU_0016185_0 chr17:31415814-31422953 3.69 4.38 NOVEL UPREG. TU_0104717_0 chr9:130697833-130698832 2.79 4.36 PROTEIN UPREG. TU_0052105_0 chr16:4785874-4786488 2.99 4.36 PROTEIN UPREG. TU_0058663_0 chr1:21795295-21850855 1.99 4.35 PROTEIN UPREG. TU_0108056_0 chr22:43527112-46638770 1.74 4.34 PROTEIN UPREG. TU_0098781_0 chr11:67151991-67154057 2.48 4.33 PROTEIN UPREG. TU_0085924_0 chr5:126233852-126241807 2.89 4.32 PROTEIN UPREG. TU_0048191_0 chr4:72423780-72424347 2.93 4.32 PROTEIN UPREG. TU_0034727_0 chr14:73508223-73508442 2.29 4.32 PROTEIN UPREG. TU_0096297_0 chr11:128342286-128353900 1.84 4.31 PROTEIN UPREG. TU_0007829_0 chr2:3625233-4275129 4.39 4.30 PROTEIN UPREG. TU_0116252_0 chr2:47449510-47467636 1.93 4.30 PROTEIN UPREG. TU_0115216_0 chr2:27179274-27177799 2.02 4.27 PROTEIN UPREG. TU_0018409_0 chr17:66013419-65059811 2.02 4.26 PROTEIN UPREG. TU_0090847_0 chr8:126511614-126519830 2.75 4.25 PROTEIN UPREG. TU_0035182_0chr14:81062781-81063412 2.22 4.25 PROTEIN UPREG. TU_0040936_0 chr3:155391785-155458298 2.10 4.26 PROTEIN UPREG. TU_0027558_0 chrX:23595491-23614435 1.66 4.25 PROTEIN UPREG. TU_0076460_0 chr10:121248954-121292235 1.68 4.24 PROTEIN UPREG. TU_0067170_0 chr1:160826739-1608726994 2.10 4.23 PROTEIN UPREG. TU_0303050_0 chr9:89409881-89512477 2.30 4.23 PROTEIN UPREG. TU_0112868_0 chr19:77590455-77402342 1.55 4.23 PROTEIN UPREG. TU_0090960_0 chr11:25059388-25060757 3.85 4.23 PROTEIN UPREG. TU_0072165_0 chr20:40142077-40204030 4.69 4.22 PROTEIN UPREG. TU_0044687_0 chr13:74756644-74954891 2.04 4.21 ncRNA UPREG. TU_0096477_0 chr11:133479414-133850753 4.43 4.21 PROTEIN UPREG. TU_0093947_0 chr11:68208575-68215218 1.41 4.20 PROTEIN UPREG. TU_0103253_0 chr9:96405246-96442373 1.69 4.20 PROTEIN UPREG. TU_0091863_0 chr11:57008498-57039966 2.69 4.20 PROTEIN UPREG. TU_0106199_0 chr22:18300042-15014411 3.94 4.20 NOVEL UPREG. TU_0090140_0 chr11:4748163-4759145 6.33 4.20 PROTEIN UPREG. TU_0103051_0 chr9:89302442-89405899 2.37 4.19 NOVEL UPREG. TU_0078290_0 chr12:32594534-32410838 3.20 4.19 PROTEIN UPREG. TU_0029336_0 chrX:70869659-70712461 1.70 4.18 PROTEIN UPREG. TU_0092155_0 chr11:60871597-60886554 1.80 4.18 PROTEIN UPREG. TU_0095597_0 chr11:114549577-114880335 1.75 4.18 PROTEIN UPREG. TU_0082724_0 chr12:120230545-120274615 1.42 4.17 PROTEIN UPREG. TU_0079770_0 chr12:55040665-55042824 4.25 4.16 PROTEIN UPREG. TU_0000263_0 chr6:4060929-4080831 1.56 4.16 NOVEL UPREG. TU_0040394_0 chr3:133418532-133441282 3.46 4.16 PROTEIN UPREG. TU_0066594_0 chr1:15424543-154257368 1.40 4.15 PROTEIN UPREG. TU_0099852_0 chr8:126515081-126519830 2.81 4.15 PROTEIN UPREG. TU_0100363_0 chr8:144891741-144899588 2.24 4.14 PROTEIN UPREG. TU_0095461_0 chr11:133751095-133757235 2.10 4.13 ncRNA UPREG. TU_0044488_0 chr13:51641093-51641310 2.76 4.13 PROTEIN UPREG. TU_0048990_0 chr4:95592056-95804933 2.30 4.13 NOVEL UPREG. TU_0078293_0 chr12:12396393-32414822 2.90 4.13 PROTEIN UPREG. TU_0046202_0 chr4:991841-1010686 2.57 4.12 PROTEIN UPREG. TU_0091866_0 chr11:57008498-57010253 2.54 4.12 PROTEIN UPREG. TU_0011133_0 chr7:94378726-94759741 1.77 4.12 PROTEIN UPREG. TU_0122941_0 chr2:234410713-234427931 3.28 4.12 PROTEIN UPREG. TU_0084131_0 chr5:13929880-13953380 2.62 4.12 NOVEL UPREG. TU_0084142_0 chr5:14017046-14021379 3.59 4.11 PROTEIN UPREG. TU_0087955_0 chr5:140931545-140931565 2.00 4.10 PROTEIN UPREG. TU_0085953_0 chr5:79410392-79410389 3.35 4.10 PROTEIN UPREG. TU_0022288_0 chr19:18357973-18360121 2.75 4.09 PROTEIN UPREG. TU_0085951_0 chr5:79366959-79414885 3.01 4.09 PROTEIN UPREG. TU_0060849_0 chr1:32572021-32574435 1.81 4.09 PROTEIN UPREG. TU_0087441_0 chr5:134934290-134942617 2.74 4.09 PROTEIN UPREG. TU_0042725_0 chr13:23148223-23200551 4.96 4.09 PROTEIN UPREG. TU_0039018_0 chr3:66510505-66634168 1.68 4.08 PROTEIN UPREG. TU_0096299_0 chr11:128340164-128347506 1.70 4.07 PROTEIN UPREG. TU_0022290_0 chr19:18357973-18359195 2.64 4.07 PROTEIN UPREG. TU_0100684_0 chr8:146190487-146191030 1.89 4.06 PROTEIN UPREG. TU_0042974_0 chr13:26148671-2614967 2.81 4.06 NOVEL UPREG. TU_0084308_0 chr5:15938753-15949124 4.08 4.06 NOVEL UPREG. TU_0082746_0 chr12:120197102-120197416 4.97 4.06 PROTEIN UPREG. TU_0014355_0 chr17:2650561-2887730 1.92 4.05 PROTEIN UPREG. TU_0114110_0 chr15:99250537-99274351 2.01 4.05 PROTEIN UPREG. TU_0096341_0 chr11:129534843-129585464 1.54 4.04 PROTEIN UPREG. TU_0052083_0 chr16:4784094-4805339 2.71 4.04 NOVEL UPREG. TU_0078296_0 chr12:32394534-32405549 2.92 4.04 PROTEIN UPREG. TU_0084126_0 chr5:13892443-13903812 3.64 4.03 NOVEL UPREG. TU_0047312_0 chr4:39217669-39222163 3.83 4.02 PROTEIN UPREG. TU_0008287_0 chr7:8119340-8268973 1.65 4.02 PROTEIN UPREG. TU_0018937_0 chr17:73714011-73714967 1.61 4.01 PROTEIN UPREG. TU_0048995_0 chr4:95805027-95808417 2.47 4.00 PROTEIN UPREG. TU_0038694_0 chr3:53810226-53855769 2.03 3.99 ncRNA UPREG. TU_0046233_0 chr4:1202157-1232168 2.45 3.99 PROTEIN UPREG. TU_0019018_0 chr17:75372094-75381243 2.25 3.98 PROTEIN UPREG. TU_0042326_0 chr

: 199123974-199125319 1.77 3.98 PROTEIN UPREG. TU_0099893_0 chr8:128817416-128819105 2.23 3.98 PROTEIN UPREG. TU_0012491_0 chr7:111304238-111362856 1.91 3.98 PROTEIN UPREG. TU_0112385_0 chr15:70816880-70864494 1.71 3.97 PROTEIN UPREG. TU_0042964_0 chr4:57020861-57038533 1.74 3.97 PROTEIN UPREG. TU_0052565_0 chr1

: 19862784-19409995 1.98 3.96 NOVEL UPREG. TU_0042717_0 chr13:25149908-23200198 4.95 3.96 PROTEIN UPREG. TU_0017374_0 chr17:43300055-43404182 1.53 3.96 PROTEIN UPREG. TU_0071058_0 chr20:20318209-20549154 2.02 3.96 PROTEIN UPREG. TU_0105741_0 chrY:6971017-6998339 2.20 3.95 PROTEIN UPREG. TU_0018995_0 chr17:74491566-74517485 1.64 3.94 PROTEIN UPREG. TU_0103055_0 chr9: 89512509-8

513285 1.92 3.93 PROTEIN UPREG. TU_0041139_0 chr3: 171237964-1712859061.91 3.93 PROTEIN UPREG. TU_0042325_0 chr3: 199124975-199143480 1.743.93 PROTEIN UPREG. TU_0020688_0 chr19: 8180054-8237335 1.80 3.93PROTEIN UPREG. TU_0118314_0 chr2: 90086923-99100654 1.78 3.92 PROTEINUPREG. TU_0017875_0 chr17: 54652767-54706896 2.33 3.92 PROTEIN UPREG.TU_0037277_0 chr3: 24134438-24511318 1.75 3.92 PROTEIN UPREG. TU_004759

_0 chr4: 40445539-40457235 1.90 3.91 PROTEIN UPREG. TU_0114108_0 chr15:99235494-99274389 2.00 3.91 ncRNA UPREG. TU_0024530_0 chr19:50889160-50909766 1.72 3.91 PROTEIN UPREG. TU_0008957_0 chr7:88308886-38325338 2.62 3.91 PROTEIN UPREG. TU_0043122_0 chr13:28983555-28989371 1.73 3.90 PROTEIN UPREG. TU_0076644_0 chr10:127398227-127398596 2.06 3.90 PROTEIN UPREG. TU_0045423_0 chr13:10055877-100125079 2.02 3.89 PROTEIN UPREG. TU_0045495_0 chr13:107720446-107737194 2.08 3.88 PROTEIN UPREG. TU_0076648_0chr10-127412714-127442685 1.64 3.88 NOVEL UPREG. TU_0088857_0 chr5:172259171-172275517 1.69 3.87 NOVEL UPREG. TU_0044453_0 chr13:51505777-51524522 2.95 3.86 NOVEL UPREG. TU_0047380_0 chr4:39217641-39222163 3.43 3.86 PROTEIN UPREG. TU_0100838_0 chr21:30508275-30510244 2.43 3.86 NOVEL UPREG. TU_0106544_0 chr22:22210421-22220506 4.27 3.85 ncRNA UPREG. TU_0100275_0 chr8:144520506-144537551 2.11 3.85 PROTEIN UPREG. TU_0057466_0 chr18:72853744-72866791 1.58 3.84 PROTEIN UPREG. TU_0040010_0 chr3:126331839-126412928 2.16 3.84 PROTEIN UPREG. TU_0042800_0 chr13:23360816-23370548 2.73 3.84 PROTEIN UPREG. TU_0112501_0 chr2:74065748-74174193 1.71 3.83 PROTEIN UPREG. TU_0053389_0 chr1

: 45673980-45701001 2.66 3.83 PROTEIN UPREG. TU_0087944_0 chr11:140874777-140978925 1.47 3.83 PROTEIN UPREG. TU_0017393_0 chr17:43389397-43390800 1.90 3.82 PROTEIN UPREG. TU_0008919_0 chr7:38257158-38271020 1.93 3.82 PROTEIN UPREG. TU_0088393_0 chr14:50259793-50367616 1.51 3.82 PROTEIN UPREG. TU_0049911_0 chr4:139304784-139382952 2.48 3.82 PROTEIN UPREG. TU_0024366_0 chr19:50100808-50104487 1.88 3.82 PROTEIN UPREG. TU_0070109_0 chr1:243979271-244159914 1.56 3.81 PROTEIN UPREG. TU_0120975_0 chr2:182104651-182107832 1.89 3.80 NOVEL UPREG. TU_0044933_0 chr18:94765992-94760688 2.52 3.80 PROTEIN UPREG. TU_0103689_0 chr9:111019219-111122750 1.75 3.80 PROTEIN UPREG. TU_0096460_0 chr11:133734857-133786962 2.09 3.79 PROTEIN UPREG. TU_0071115_0 chr20:24934888-24986948 1.48 3.79 PROTEIN UPREG. TU_0093788_0 chr11:67153661-67153870 2.48 3.79 PROTEIN UPREG. TU_0047591_0 chr4:40457999-40508855 1.79 3.79 PROTEIN UPREG. TU_0112336_0 chr15:70880765-70838345 1.83 3.78 PROTEIN UPREG. TU_0086664_0 chr1:154481433-154485049 2.29 3.78 PROTEIN UPREG. TU_0018812_0 chr17:72119376-72151549 3.38 3.78 PROTEIN UPREG. TU_0110225_0 chr15:48510091-48912722 3.60 3.78 ncRNA UPREG. TU_0054545_0 chr16:79431010-79431652 10.28 3.78 PROTEIN UPREG. TU_0107643_0 chr22:39072496-39093168 1.36 3.78 PROTEIN UPREG. TU_0025230_0 chr19:55992773-56000199 1.86 3.78 PROTEIN UPREG. TU_0012480_0 chr7:111153704-111155311 1.81 3.77 PROTEIN UPREG. TU_0070821_0 chr20:8997167-9409281 1.64 3.77 PROTEIN UPREG. TU_0103873_0 chr9:115151636-115178183 1.52 3.77 PROTEIN UPREG. TU_0018813_0 chr17:72128611-72133119 3.56 3.76 NOVEL UPREG. TU_0112004_0 chr18:67644390-67650387 3.56 3.76 PROTEIN UPREG. TU_0043118_0 chr13:28981555-29067829 1.76 3.76 NOVEL UPREG. TU_0112003_0 chr15:67645590-67775246 3.12 3.76 NOVEL UPREG. TU_0060448_0 chr1:28438629-28450150 2.23 3.75 PROTEIN UPREG. TU_0122972_0 chr2:236068012-236482693 1.69 3.75 NOVEL UPREG. TU_0106545_0 chr22:22218478-22219162 3.99 3.74 PROTEIN UPREG. TU_0087288_0 chr5:133755241-133766074 1.85 3.74 ncRNA UPREG. TU_0025312_0 chr19:57059515-57145170 1.89 3.74 PROTEIN UPREG. TU_0079679_0 chr12:54760142-54783545 1.58 3.73 PROTEIN UPREG. TU_0074564_0 chr10:64241786-64246112 2.62 3.73 PROTEIN UPREG. TU_0106189_0 chr22:18235213-18328816 1.82 3.73 PROTEIN UPREG. TU_0078994_0 chr12:49412412-49428706 1.41 3.72 ncRNA UPREG. TU_0003229_0 chr6:41598975-41621874 2.05 3.72 PROTEIN UPREG. TU_0040937_0 chr3:155439710-155458293 1.96 3.72 PROTEIN UPREG. TU_0040093_0 chr5:128880751-128874336 1.87 3.72 NOVEL UPREG. TU_0106542_0 chr22:22213315-22220505 3.77 3.71 PROTEIN UPREG. TU_0019375_0 chr17:77608812-77816980 1.63 3.71 PROTEIN UPREG. TU_0042568_0 chr15:20264762-20334986 1.85 3.71 PROTEIN UPREG. TU_0103386_0 chr9:99895734-99118148 1.89 3.71 PROTEIN UPREG. TU_0030004_0 chrX:100534013-100534540 1.84 3.71 NOVEL UPREG. TU_0089906_0 chr11:1042845-1045785 2.94 3.71 NOVEL UPREG. TU_0089014_0 chr9:176014905-176015351 2.01 3.71 ncRNA UPREG. TU_0056173_0 chr18:22525074-22557627 3.31 3.70 PROTEIN UPREG. TU_0052880_0 chr16:28393117-28411069 1.48 3.70 PROTEIN UPREG. TU_0100355_0 chr8:144884230-144910177 2.00 3.69 PROTEIN UPREG. TU_0096216_0 chr11:125271293-125271517 2.08 3.69 PROTEIN UPREG. TU_0092161_0 chr11:60884289-60892364 1.99 3.68 PROTEIN UPREG. TU_0086926_0 chr5:126241958-126394149 2.27 3.68 NOVEL UPREG. TU_0088230_0 chr5:148864170-148864752 1.94 3.68 ncRNA UPREG. TU_0099940_0 chr8:129855546-129182684 1.61 3.68 PROTEIN UPREG. TU_0089017_0 chr5:176222085-176240501 10.21 3.67 PROTEIN UPREG. TU_0078586_0 chr12:46643629-46648944 1.47 3.67 PROTEIN UPREG. TU_0053467_0 chr16:51028455-51138080 2.19 3.67 PROTEIN UPREG. TU_0089452_0 chr5:179258704-179258997 1.62 3.67 PROTEIN UPREG. TU_0076329_0 chr10:115501382-115531028 2.60 3.67 PROTEIN UPREG. TU_0047688_0 chr4:42105164-42354144 1.68 3.67 PROTEIN UPREG. TU_0059142_0 chr1:16203274-16206548 12.41 3.67 PROTEIN UPREG. TU_0116906_0 chr2:63155968-53138462 2.81 3.66 PROTEIN UPREG. TU_0000154_0 chr6:3063923-3099152 1.53 3.66 PROTEIN UPREG. TU_0088782_0 chr5:170625426-170659598 1.78 3.66 NOVEL UPREG. TU_0089905_0 chr11:1042845-1045785 2.77 3.66 PROTEIN UPREG. TU_0101704_0 chr9:3265495-3516005 2.33 3.64 ncRNA UPREG. TU_0044897_0 chr15:94746498-94760688 2.17 3.64 PROTEIN UPREG. TU_0071059_0 chr20:20549245-20641260 2.39 3.64 ncRNA UPREG. TU_0046268_0 chr4:1199698-1211108 1.93 3.63 PROTEIN UPREG. TU_0071601_0chr20:32827590-32828002 1.75 3.62 PROTEIN UPREG. TU_0100712_0 chr21:15258179-15359100 2.14 3.62 PROTEIN UPREG. TU_0092158_0 chr11:60885030-60893249 1.45 3.62 PROTEIN UPREG. TU_0091402_0 chr11:46255779-46299542 1.71 3.62 PROTEIN UPREG. TU_0039019_0 chr3:66376322-66514060 1.50 3.62 PROTEIN UPREG. TU_0100378_0 chr8:144899799-144900640 2.00 3.62 NOVEL UPREG. TU_0112025_0 chr15:67780574-67782345 3.42 3.62 PROTEIN UPREG. TU_0106031_0 chr22:16336630-16412806 2.01 3.62 PROTEIN UPREG. TU_0050785_0 chr4:174895560-174453821 2.38 3.61 PROTEIN UPREG. TU_0058834_0 chr1:11768665-11783670 1.50 3.61 PROTEIN UPREG. TU_0039496_0 chr3:106753939-106754201 1.99 3.61 ncRNA UPREG. TU_0098397_0 chr8:69379259-69406175 2.73 3.61 PROTEIN UPREG. TU_0017847_0 chr17:54188675-54413808 2.82 3.61 PROTEIN UPREG. TU_0108299_0 chr22:49267227-49270226 2.03 3.60 PROTEIN UPREG. TU_0076846_0 chr10:135042714-155056676 2.27 3.59 PROTEIN UPREG. TU_0096351_0 chr11:129611827-129689996 1.61 3.59 PROTEIN UPREG. TU_0019298_0 chr17:77242472-77300154 1.51 3.59 PROTEIN UPREG. TU_0057465_0 chr18:72830973-729737

9 1.55 3.59 PROTEIN UPREG. TU_0013475_0 chr2: 148137800-148212387 1.743.59 PROTEIN UPREG. TU_00

1426_0 chr6: 28688044-28662198 2.58 3.59 NOVEL UPREG. TU_01

541_0 chr22: 22209111-22219162 4.02 3.58 PROTEIN UPREG. TU_0071803_0chr10: 19005564-19007053 1.94 3.58 PROTEIN UPREG. TU_0010100_0 chr3:129253916-129269610 1.39 3.58 PROTEIN UPREG. TU_0001432_0 chr6:28978594-28999755 1.33 3.58 PROTEIN UPREG. TU_0076643_0 chr10:127398227-127407663 1.73 3.57 PROTEIN UPREG. TU_0089137_0 chr5:176814485-176815986 1.93 3.57 PROTEIN UPREG. TU_0098700_0 chr8: 87

06988-82333612 1.76 3.57 PROTEIN UPREG. TU_0093785_0 chr11:67186209-67198838 3.74 3.57 NOVEL UPREG. TU_0056163_0 chr18:22477042-22477665 3.05 3.57 PROTEIN UPREG. TU_0067222_0 chr1:164063363-194147501 1.63 3.57 PROTEIN UPREG. TU_0052172_0 chr16:8799176-8790379 1.61 3.57 PROTEIN UPREG. TU_0008350_0 chr7:16852301-16712672 1.45 3.57 PROTEIN UPREG. TU_0035610_0 chr14: 935

0687-93582188 2.08 3.56 PROTEIN UPREG. TU_0000168_0 chr6:3100128-3102765 2.10 3.56 PROTEIN UPREG. TU_0019649_0 chr3:115180992-115164502 1.72 3.56 PROTEIN UPREG. TU_0052843_0 chr16:27143818-27187907 1.42 3.56 NOVEL UPREG. TU_0024950_0 chr19:54450100-54432968 2.11 3.55 PROTEIN UPREG. TU_0008504_0 chr7:24656812-24693891 1.99 3.55 PROTEIN UPREG. TU_0061102_0 chr1:35571678-35795597 1.44 3.55 PROTEIN UPREG. TU_0032850_0 chr14: 36736878:36788106 2.36 3.55 ncRNA UPREG. TU_0045241_0 chr4: 1198292-1167180 2.533.55 NOVEL UPREG. TU_00

499_0 chr7: 24236191-24236455 5.44 3.54 PROTEIN UPREG. TU_0100172_0chr8: 142471307-142511866 1.79 3.54 NOVEL UPREG. TU_0085543_0 chr5:110311813-110312092 1.53 3.53 PROTEIN UPREG. TU_0072450_0 chr20:44161989

-44747359 1.83 3.53 NOVEL UPREG. TU_0094972_0 chr15: 94755980-947597352.15 3.53 PROTEIN UPREG. TU_0093950_0 chr11: 6

21474

-68215218 1.49 3.53 PROTEIN UPREG. TU_0006239_0 chr6: 13864933

-133671427 2.22 3.53 PROTEIN UPREG. TU_0063894_0 chr1:150944684-150070988 1.54 3.52 PROTEIN UPREG. TU_0078675_0 chr12:47602047-47602939 1.58 3.52 PROTEIN UPREG. TU_0052150_0 chr16:8799176-65-64674 1.42 3.52 NOVEL UPREG. TU_0112011_0 chr15:67762926-67783593 2.66 3.52 PROTEIN UPREG. TU_0041581_0 chr3:185450132-185459240 1.77 3.52 PROTEIN UPREG. TU_0017269_0 chr17:42127174-421

9979 1.59 3.52 PROTEIN UPREG. TU_010138_0 chr6: 94055563-94056963 1.613.52 PROTEIN UPREG. TU_0078683_0 chr12: 47503989-47604485 1.69 3.52PROTEIN UPREG. TU_0099209_0 chr11: 6453771-6453210 1.44 3.51 ncRNAUPREG. TU_004519

_0 chr15: 97851959-97852689 1.98 3.51 PROTEIN UPREG. TU_0050499_0 chr4:159862572-156862939 1.82 3.51 PROTEIN UPREG. TU_0088025_0 chr5:142130154-142254088 1.89 3.51 PROTEIN UPREG. TU_0052554_0 chr16:10329285-19424714 1.78 3.51 PROTEIN UPREG. TU_0085663_0 chr5:70918890-75990273 2.39 3.51 PROTEIN UPREG. TU_0101238_0 chr21:41610496-41851888 1.89 3.50 PROTEIN UPREG. TU_0098659_0 chr8:82355436-82355877 4.15 3.49 PROTEIN UPREG. TU_0100271_0 chr8:144522379-144537551 1.33 3.49 PROTEIN UPREG. TU_0013258_0 chr7:139750340-139773086 1.85 3.49 PROTEIN UPREG. TU_0122559_0 chr2:224338108-224338327 2.32 3.49 PROTEIN UPREG. TU_0062947_0 chr1:212567070-212567723 1.74 3.48 PROTEIN UPREG. TU_0101300_0 chr21:42512421-42593934 1.60 3.48 PROTEIN UPREG. TU_0105268_0 chr3:1382318731-138277254 1.49 3.47 PROTEIN UPREG. TU_0080269_0 chr12:62524730-62664317 2.05 3.47 PROTEIN UPREG. TU_0051992_0 chr6:31939105-31955076 1.56 3.47 PROTEIN UPREG. TU_0018485_0 chr17:76458432-70490451 1.58 3.47 ncRNA UPREG. TU_0050493_0 chr1:28705947-28706605 1.60 2.46 PROTEIN UPREG. TU_0085975_0 chr5:79478814-79495113 1.91 3.46 PROTEIN UPREG. TU_0018919_0 chr17:73678343-73714570 1.48 3.46 ncRNA UPREG. TU_0054534_0 chr16:79404014-79431652 9.85 3.46 PROTEIN UPREG. TU_0076107_0 chr10:104464315-104488075 1.67 3.45 ncRNA UPREG. TU_0069658_0 chr1:229724782-229731269 1.75 3.45 NOVEL UPREG. TU_0120387_0 chr2:170267824-170281385 2.10 3.45 PROTEIN UPREG. TU_0013665_0 chr17:24073407-24077926 1.52 3.45 ncRNA UPREG. TU_0070414_0 chr20:3254059-1303172 1.65 3.45 NOVEL UPREG. TU_0072624_0 chr20:47335522-47338977 1.65 3.45 PROTEIN UPREG. TU_0012495_0 chr7:111373031-111411626 2.29 3.45 PROTEIN UPREG. TU_0076659_0 chr10:177514501-127576128 1.31 3.45 PROTEIN UPREG. TU_0088525_0 chr5:156525701-156755173 1.53 3.45 PROTEIN UPREG. TU_0046096_0 chr4:759449-809939 2.01 3.44 ncRNA UPREG. TU_0074332_0 chr10:43420869-43421283 1.52 3.44 PROTEIN UPREG. TU_0082983_0 chr12:121778239-121779189 2.65 3.44 PROTEIN UPREG. TU_0008361_0 chr2:16750923-16790805 1.58 3.44 PROTEIN UPREG. TU_0081443_0 chr1:38032067-38039550 1.67 3.44 PROTEIN UPREG. TU_0042715_0 chr13:25148223-23204319 3.68 3.43 ncRNA UPREG. TU_0119128_0 chr2:118310197-118313068 1.62 3.43 PROTEIN UPREG. TU_0112349_0 chr15:70834440-70835126 1.67 3.43 PROTEIN UPREG. TU_0027543_0 chrX:21921233-21922374 2.48 3.43 PROTEIN UPREG. TU_0082552_0 chr1:47889058-47552320 1.83 3.43 ncRNA UPREG. TU_0080791_0 chr4:174322695-174323924 2.13 3.41 PROTEIN UPREG. TU_0048346_0 chr4:77175264-77176185 2.48 3.41 NOVEL UPREG. TU_0093068_0 chr11:64956618-64961189 2.13 3.41 PROTEIN UPREG. TU_0033869_0 chr14:60248258-60250801 1.71 3.41 PROTEIN UPREG. TU_0000031_0 chr6:2190031-2190908 2.44 3.41 PROTEIN UPREG. TU_0082131_0 chr12:111152572-111152227 1.89 3.40 PROTEIN UPREG. TU_0038169_0 chr3:49035494-49041923 1.35 3.40 NOVEL UPREG. TU_0044898_0 chr13:94753009-94760688 2.11 3.40 PROTEIN UPREG. TU_0089144_0 chrS:176814485-176815986 1.86 3.40 PROTEIN UPREG. TU_0094504_0 chr11:74812477-74817273 2.40 3.40 PROTEIN UPREG. TU_0035633_0 chr14:94304291-94305127 2.17 3.40 PROTEIN UPREG. TU_0085819_0 chrS:75734806-76039614 1.64 3.40 PROTEIN UPREG. TU_0061431_0 chr1:37961347-37973585 2.62 3.40 NOVEL UPREG. TU_0078299_0 chr12:32290896-32292169 3.67 3.39 PROTEIN UPREG. TU_0004059_0 chr6:52976578-53054598 1.65 3.39 PROTEIN UPREG. TU_0098927_0 chr8:95722432-95788870 1.48 3.39 ncRNA UPREG. TU_0013856_0 chr7:155957953-156090620 2.50 3.39 PROTEIN UPREG. TU_0068377_0 chr1:201452418-201458956 1.84 3.39 NOVEL UPREG. TU_0101035_0 chr21:35419563-36421930 1.84 3.39 PROTEIN UPREG. TU_0062957_0 chr1:54089897-54128073 1.43 3.39 PROTEIN UPREG. TU_0099854_0 chr8:127633901-127639897 1.65 3.38 PROTEIN UPREG. TU_0048743_0 chr4:87924751-87955166 1.47 3.38 PROTEIN UPREG. TU_0086478_0 chr5:102510255-102521832 1.95 3.38 PROTEIN UPREG. TU_0120565_0 chr2:172672776-172675279 4.31 3.38 PROTEIN UPREG. TU_0122360_0 chr2:219554051-219557439 2.92 3.38 PROTEIN UPREG. TU_0092154_0 chr11:60857271-60874474 1.44 3.37 PROTEIN UPREG. TU_0015718_0 chr17:24095069-24100305 1.64 3.37 PROTEIN UPREG. TU_0039284_0 chr3:95208686-95249573 2.23 3.37 PROTEIN UPREG. TU_0082089_0 chr12:111082307-111187476 1.44 3.37 PROTEIN UPREG. TU_0035148_0 chr14:81009021-81069951 1.64 3.37 PROTEIN UPREG. TU_0054849_0 chr16:87403253-87406669 1.47 3.37 PROTEIN UPREG. TU_0113376_0 chr15:87432650-87545107 2.13 3.36 PROTEIN UPREG. TU_0019481_0 chr17:77998514-77999441 1.55 3.36 PROTEIN UPREG. TU_0007004_0 chr6:158396021-158440190 1.47 3.36 PROTEIN UPREG. TU_0092190_0 chr11:60876795-60877493 1.85 3.36 ncRNA UPREG. TU_0001996_0 chr6:31941546-31959679 1.43 3.36 NOVEL UPREG. TU_0066689_0 chr1:154509233-154510967 1.61 3.36 PROTEIN UPREG. TU_0035151_0 chr14:81015445-81021875 2.00 3.35 PROTEIN UPREG. TU_0092866_0 chr11:55975211-63975675 3.20 3.35 PROTEIN UPREG. TU_0050482_0 chr4:156807332-156877628 1.69 3.35 PROTEIN UPREG. TU_0022391_0 chr19:19076718-19094443 1.60 3.35 PROTEIN UPREG. TU_0048729_0 chr4:87734463-87924734 1.74 3.35 PROTEIN UPREG. TU_0103472_0 chr9:100534124-100570357 1.61 3.35 PROTEIN UPREG. TU_0087465_0 chr5:136431191-136431490 2.47 3.35 PROTEIN UPREG. TU_0058833_0 chr1:11768665-11788581 1.45 3.34 PROTEIN DOWNREG. TU_0009047_0 chr7:41967123-41970103 0.65 −3.35 PROTEIN DOWNREG. TU_0020039_0 chr19:2948637-2980244 0.65 −3.36 PROTEIN DOWNREG. TU_0024046_0 chr19:47194316-47201741 0.53 −3.36 PROTEIN DOWNREG. TU_0120035_0 chr:154042114-154043553 0.49 −3.36 PROTEIN DOWNREG. TU_0014542_0 chr17:4790024-47790984 0.77 −3.36 PROTEIN DOWNREG. TU_0058703_0 chr1:10857547-10613394 0.66 −3.37 NOVEL DOWNREG. TU_0084922_0 chrS:44337219-44338127 0.51 −3.37 PROTEIN DOWNREG. TU_0067333_0 chr1:167362572-167539064 0.68 −3.37 PROTEIN DOWNREG. TU_0030086_0 chrX:101794939-101798995 0.64 −3.37 PROTEIN DOWNREG. TU_0031101_0 chrX:134247418-134254372 0.69 −3.37 PROTEIN DOWNREG. TU_0063762_0 chr1:87666944-87583813 0.66 −3.38 PROTEIN DOWNREG. TU_0107584_0 chr22:38075931-38123808 0.66 −3.38 PROTEIN DOWNREG. TU_0102296_0 chr9:34979701-34988409 0.57 −3.38 PROTEIN DOWNREG. TU_0038485_0 chr3:51981847-51958558 0.65 −3.38 PROTEIN DOWNREG. TU_0062948_0 chr1:53744574-53746867 0.48 −3.38 PROTEIN DOWNREG. TU_0092656_0 chr11:63282470-63288729 0.73 −3.38 PROTEIN DOWNREG. TU_0035606_0 chr14:95470258-93500717 0.58 −3.38 PROTEIN DOWNREG. TU_0053588_0 chr18:10470831-10478690 0.58 −3.38 PROTEIN DOWNREG. TU_0056465_0 chr18:41558112-41584622 0.49 −3.39 PROTEIN DOWNREG. TU_0002739_0 chr6:35321958-35328561 0.55 −3.39 PROTEIN DOWNREG. TU_0030147_0 chrx:102727067-102729284 0.65 −3.39 NOVEL DOWNREG. TU_0030209_0 chrx:103250961-103253228 0.68 −3.39 ncRNA DOWNREG. TU_0068206_0 chr1:200132176-200134973 0.60 −3.39 PROTEIN DOWNREG. TU_0081627_0 chr12:108186419-108190411 0.63 −3.40 PROTEIN DOWNREG. TU_0088194_0 chr2:200132176-200182322 0.59 −3.40 PROTEIN DOWNREG. TU_0049308_0 chr4:104220026-104220361 0.46 −3.40 NOVEL DOWNREG. TU_0068431_0 chr1:202350966-202363482 0.62 −3.40 PROTEIN DOWNREG. TU_0073506_0 chr10:7630096-7723984 0.60 −3.40 PROTEIN DOWNREG. TU_0054695_0 chr16:83411108-83499914 0.62 −3.40 PROTEIN DOWNREG. TU_0012556_0 chr7:115934290-115935899 0.50 −3.41 PROTEIN DOWNREG. TU_0018647_0 chr17:71259157-71294839 0.74 −3.41 NOVEL DOWNREG. TU_0030577_0 chrX:118036531-118035860 0.43 −3.41 PROTEIN DOWNREG. TU_0089981_0 chr11:2248339-2247566 0.52 −3.41 PROTEIN DOWNREG. TU_0000858_0 chr6:19947236-19950403 0.56 −3.41 PROTEIN DOWNREG. TU_0002212_0 chr8:32224073-32229328 0.58 −3.41 PROTEIN DOWNREG. TU_0024749_0 chr10:52937559-52939100 0.58 −3.41 PROTEIN DOWNREG. TU_0102225_0 chr21:40161189-10181418 0.52 −3.41 ncRNA DOWNREG. TU_0100030_0 chrX:134893580-134659310 0.41 −3.41 PROTEIN DOWNREG. TU_0102256_0 chr9:34356684-34366854 0.56 −3.41 PROTEIN DOWNREG. TU_0039040_0 chr3:69107066-69108860 0.62 −3.42 ncRAN DOWNREG. TU_0115808_0 chr2:37722515-37725828 0.61 −3.42 PROTEIN DOWNREG. TU_0115807_0 chr2:37722515-37729828 0.61 −3.42 NOVEL DOWNREG. TU_0038811_0 chr8:57890130-58970834 0.43 −3.43 PROTEIN DOWNREG. TU_0107000_0 chr22:29790122-29830660 0.60 −3.43 PROTEIN DOWNREG. TU_0065120_0 chr1:144274405-144279906 0.53 −3.43 PROTEIN DOWNREG. TU_0065093_0 chr1:144167535-144181746 0.72 −3.43 PROTEIN DOWNREG. TU_0066887_0 chr1:158352167-158370985 0.56 −3.44 PROTEIN DOWNREG. TU_0034681_0 chr14:75248251-73250867 0.61 −3.44 PROTEIN DOWNREG. TU_0064872_0 chr1:115373945-115394701 0.60 −3.44 PROTEIN DOWNREG. TU_0115146_0 chr2:26806070-26809827 0.49 −3.44 PROTEIN DOWNREG. TU_0023552_0 chr19:43433715-43439100 0.52 −3.44 PROTEIN DOWNREG. TU_0013056_0 chr2:134269121-134268574 0.41 −3.44 PROTEIN DOWNREG. TU_0078015_0 chr12:21809160-21817495 0.61 −3.45 PROTEIN DOWNREG. TU_0010849_0 chr7:84462824-84464278 0.41 −3.45 PROTEIN DOWNREG. TU_0018278_0 chr17:62235564-62237319 0.62 −3.45 PROTEIN DOWNREG. TU_0106896_0 chr22:28206216-28217370 0.46 −3.46 PROTEIN DOWNREG. TU_0086308_0 chr6:95168335-95184222 0.54 −3.46 PROTEIN DOWNREG. TU_0053500_0 chr1:19842799-19857540 0.66 −3.46 PROTEIN DOWNREG. TU_0030156_0 chrX:102740504-102752163 0.61 −3.46 PROTEIN DOWNREG. TU_0053209_0 chr16:30815439-60839057 0.45 −3.46 PROTEIN DOWNREG. TU_0102372_0 chr9:35672000-35681306 0.58 −3.46 PROTEIN DOWNREG. TU_0040491_0 chr3:134987802-134980829 0.35 −3.46 PROTEIN DOWNREG. TU_0063025_0 chr1:54832256-54849445 0.56 −3.46 PROTEIN DOWNREG. TU_0016741_0 chr17:37808007-37818100 0.61 −3.47 PROTEIN DOWNREG. TU_0073672_0 chr12:65272841-55276238 0.78 −3.47 NOVEL DOWNREG. TU_0072214_0 chr20:42166331-42122501 0.45 −3.47 PROTEIN DOWNREG. TU_0069254_0 chr3:223745864-223750945 0.54 −3.48 PROTEIN DOWNREG. TU_0014474_0 chr17:4410320-4410814 0.34 −3.48 PROTEIN DOWNREG. TU_0082036_0 chr6:31975375-31977685 0.61 −3.48 ncRNA DOWNREG. TU_0115605_0 chr2:37722515-37727509 0.64 −3.48 PROTEIN DOWNREG. TU_0106457_0 chr22:21742726-21732216 0.56 −3.48 PROTEIN DOWNREG. TU_0100880_0 chr21:32808766-62809639 0.62 −3.48 PROTEIN DOWNREG. TU_0028060_0 chrX:64873768-64873981 0.59 −3.48 PROTEIN DOWNREG. TU_0183717_0 chr9:112675354-112576369 0.59 −3.48 PROTEIN DOWNREG. TU_0016732_0 chr17:37807991-37828819 0.65 −3.48 PROTEIN DOWNREG. TU_0075679_0 chr10:96987317-970405910 0.65 −3.48 PROTEIN DOWNREG. TU_0108979_0 chr15:34659121-34889737 0.68 −3.48 PRTEIN DOWNREG. TU_0039868_0 chr3:123526763-123543198 0.51 −3.48 PROTEIN DOWNREG. TU_0032236_0 chr14:22839081-22833882 0.61 −3.48 PROTEIN DOWNREG. TU_0103902_0 chr9:115957988-116128421 0.59 −3.49 PROTEIN DOWNREG. TU_0064251_0 chr6:71589234-71069482 0.38 −3.49 PROTEIN DOWNREG. TU_0116344_0 chr2:27568254-27571682 0.64 −3.49 NOVEL DOWNREG. TU_0096307_0 chr11:7977293-7976927 0.69 −3.49 NOVEL DOWNREG. TU_0020914_0 chr19:9718612-9723799 0.47 −3.49 PROTEIN DOWNREG. TU_0014009_0 chr2:158823186-158930217 0.48 −3.50 PROTEIN DOWNREG. TU_0111467_0 chr15:62817064-62854842 0.58 −3.50 NOVEL DOWNREG. TU_0058552_0 chr6:257103852-157120456 0.64 −3.50 PROTEIN DOWNREG. TU_0016616_0 chr17:36992068-37034423 0.44 −3.50 PROTEIN DOWNREG. TU_0109820_0 chr15:41600571-41611159 0.56 −3.51 PROTEIN DOWNREG. TU_0083744_0 chr5:236838-297985 0.58 −3.51 PROTEIN DOWNREG. TU_0038899_0 chr3:58465926-58495812 0.58 −3.51 PROTEIN DOWNREG. TU_0018817_0 chr17:72185287-72184800 0.61 −3.51 PROTEIN DOWNREG. TU_0096362_0 chr11:129779777-129794214 0.56 −3.51 ncRNA DOWNREG. TU_0104765_0 chr9:131134480-131144297 0.53 −3.51 PROTEIN DOWNREG. TU_0047809_0 chr4:52581019-52582331 0.62 −3.52 PROTEIN DOWNREG. TU_0114638_0 chr2:11804195-11654972 0.68 −3.52 PROTEIN DOWNREG. TU_0110215_0 chr15:43246574-43254766 0.63 −3.52 PROTEIN DOWNREG. TU_0117024_0 chr2:66525747-66653430 0.61 −3.52 PROTEIN DOWNREG. TU_0109004_0 chr15:39178588-35180010 0.39 −3.53 PROTEIN DOWNREG. TU_0114005_0 chr15:97462760-97493368 0.56 −3.53 PROTEIN DOWNREG. TU_0079534_0 chr12:53260191-53268540 0.41 −3.53 PROTEIN DOWNREG. TU_0068435_0 chr1:202366748-202385528 0.62 −3.53 PROTEIN DOWNREG. TU_0014730_0 chr17:7034460-7061662 0.61 −3.53 PROTEIN DOWNREG. TU_0111099_0 chr15:57738640-57756015 0.70 −3.54 PROTEIN DOWNREG. TU_0079355_0 chr12:51906987-51912605 0.54 −3.54 PROTEIN DOWNREG. TU_0107389_0 chr22:36670710-36671784 0.59 −3.54 PROTEIN DOWNREG. TU_0105434_0 chr9:138991774-138996018 0.54 −3.54 ncRNA DOWNREG. TU_0122441_0 chr2:220000172-220002664 0.38 −3.54 PROTEIN DOWNREG. TU_0074041_0 chr10:29785041-30865975 0.84 −3.55 PROTEIN DOWNREG. TU_0114819_0 chr2:23779564-23785016 0.65 −3.55 PROTEIN DOWNREG. TU_0013666_0 chr7:150180552-150189309 0.34 −3.55 PROTEIN DOWNREG. TU_0036844_0 chr3:9930878-9933062 0.54 −3.56 PROTEIN DOWNREG. TU_0014467_0 chr17:4407802-4410614 0.49 −3.56 NOVEL DOWNREG. TU_0086397_0 chr14:104617328-104624500 0.45 −3.56 PROTEIN DOWNREG. TU_0014721_0 chr17:6882853-6884238 0.60 −3.57 PROTEIN DOWNREG. TU_0061867_0 chr1:41618433-41621890 0.61 −3.57 PROTEIN DOWNREG. TU_0090901_0 chr11:20081238-20099725 0.60 −3.57 PROTEIN DOWNREG. TU_0089503_0 chr5:179949721-179951068 0.47 −3.57 NOVEL DOWNREG. TU_0112056_0 chr15:69658838-69878469 0.46 −3.57 NOVEL DOWNREG. TU_0052454_0 chr16:15702084-15702374 0.40 −3.57 PROTEIN DOWNREG. TU_0004248_0 chr6:70983350-71069482 0.52 −3.57 PROTEIN DOWNREG. TU_0111118_0 chr15:58426685-58428568 0.59 −3.58 PROTEIN DOWNREG. TU_0047256_0 chr4:38781223-38804733 0.63 −3.58 PROTEIN DOWNREG. TU_0092308_0 chr11:61385022-61325568 0.62 −3.58 PROTEIN DOWNREG. TU_0037381_0 chr3:33159367-33165995 0.70 −3.59 PROTEIN DOWNREG. TU_0088765_0 chr5:168737435-169749043 0.53 −3.60 PROTEIN DOWNREG. TU_0039072_0 chr3:70098064-70100160 0.63 −3.60 NOVEL DOWNREG. TU_0112059_0 chr15:69667695-69691724 0.41 −3.60 PROTEIN DOWNREG. TU_0030975_0 chrX:130235170-130235814 0.49 −3.60 PROTEIN DOWNREG. TU_0038532_0 chr3:52258212-52287726 0.77 −3.60 PROTEIN DOWNREG. TU_0014418_0 chr17:3748115-3749717 0.39 −3.60 PROTEIN DOWNREG. TU_0081986_0 chr6:31791087-31793378 0.48 −3.61 PROTEIN DOWNREG. TU_0111109_0 chr15:53426655-58477514 0.86 −3.61 PROTEIN DOWNREG. TU_0064151_0 chr1:98933815-98937074 0.46 −3.61 PROTEIN DOWNREG. TU_0111253_0 chr15:81121812-61151157 0.63 −3.61 PROTEIN DOWNREG. TU_0058947_0 chr1:13782811-13817026 0.61 −3.62 PROTEIN DOWNREG. TU_0031484_0 chrX:151890690-151832673 0.59 −3.62 PROTEIN DOWNREG. TU_0076212_0 chr10:105781059-105835687 0.47 −3.62 PROTEIN DOWNREG. TU_0062567_0 chr1:47050692-47056967 0.47 −3.62 NOVEL DOWNREG. TU_0020667_0 chr19:7888598-7889980 0.41 −3.62 PROTEIN DOWNREG. TU_0029358_0 chrX:71268703-71268507 0.66 −3.63 PROTEIN DOWNREG. TU_0065339_0 chr1:148457403-148475104 0.56 −3.65 PROTEIN DOWNREG. TU_0063769_0 chr1:87583567-87587259 0.58 −3.65 NOVEL DOWNREG. TU_0036395_0 chr14:104617328-104623671 0.53 −3.63 PROTEIN DOWNREG. TU_0103872_0 chr9:115178483-115203441 0.59 −3.63 PROTEIN DOWNREG. TU_0050244_0 chr4:148585059-148685550 0.63 −3.63 PROTEIN DOWNREG. TU_0031913_0 chr14:20554755-20563715 0.64 −3.63 PROTEIN DOWNREG. TU_0065343_0 chr1:148501147-148501585 0.37 −3.63 PROTEIN DOWNREG. TU_0084948_0 chr5:50715235-50726033 0.68 −3.64 PROTEIN DOWNREG. TU_0090542_0 chr11:8672475-8549482 0.64 −3.64 PROTEIN DOWNREG. TU_0120044_0 chr2:155422693-155423038 0.26 −3.64 PROTEIN DOWNREG. TU_0023267_0 chr19:40937280-40940189 0.52 −3.84 PROTEIN DOWNREG. TU_0023553_0 chr19:4543319-43434071 0.51 −3.85 PROTEIN DOWNREG. TU_0115806_0 chr2:37722515-37725553 0.60 −3.65 PROTEIN DOWNREG. TU_0085256_0 chr5:59099579-55100724 0.53 −3.65 PROTEIN DOWNREG. TU_0038056_0 chr9:48563574-48623119 0.68 −3.65 PROTEIN DOWNREG. TU_0022088_0 chr10:168647988-16923718 0.55 −3.65 ncRNA DOWNREG. TU_0088408_0 chr12:129197899-129212499 0.58 −3.85 PROTEIN DOWNREG. TU_0059155_0 chr1:16397144-16405288 0.61 −3.85 PROTEIN DOWNREG. TU_0046595_0 chr4:3264594-3411502 0.68 −3.65 PROTEIN DOWNREG. TU_0039476_0 chr8:108331106-108578694 0.58 −3.66 PROTEIN DOWNREG. TU_0091498_0 chr11:46834081-46889744 0.65 −3.66 PROTEIN DOWNREG. TU_0098359_0 chr8:68585438-64499042 0.45 −3.66 PROTEIN DOWNREG. TU_0046627_0 chr4:3795533-3740037 0.45 −3.67 NOVEL DOWNREG. TU_0103946_0 chr9:116821701-116822181 0.48 −3.67 PROTEIN DOWNREG. TU_0008057_0 chr7:5519816-5836775 0.62 −3.67 PROTEIN DOWNREG. TU_0180219_0 chr8:143549604-143556275 0.59 −3.67 PROTEIN DOWNREG. TU_0087532_0 chr5:157802644-137810548 0.53 −3.68 PROTEIN DOWNREG. TU_0066743_0 chr1:154859563-154862200 0.43 −3.68 PROTEIN DOWNREG. TU_0052586_0 chr16:19637116-19779369 0.64 −3.68 PROTEIN DOWNREG. TU_0075308_0 chr10:88708340-88712998 0.51 −3.68 PROTEIN DOWNREG. TU_0032240_0 chr14:22894093-22905632 0.57 −3.68 PROTEIN DOWNREG. TU_0046399_0 chr4:2031053-2040569 0.44 −3.70 PROTEIN DOWNREG. TU_0081487_0 chr12:104248577-104289423 0.56 −3.70 PROTEIN DOWNREG. TU_0096978_0 chr8:22133174-22140355 0.47 −3.70 PROTEIN DOWNREG. TU_0054692_0 chr16:83411105-83900616 0.62 −3.70 PROTEIN DOWNREG. TU_0067818_0 chr1:180509414-180511335 0.72 −3.71 PROTEIN DOWNREG. TU_0098841_0 chr8:92088228-92039575 0.39 −3.71 PROTEIN DOWNREG. TU_0121595_0 chr2:262193170-262196672 0.62 −3.71 PROTEIN DOWNREG. TU_0023218_0 chr18:40679964-40694184 0.55 −3.71 PROTEIN DOWNREG. TU_0112386_0 chr15:71818130-71820041 0.55 −3.71 PROTEIN DOWNREG. TU_0024601_0 chr19:51603296-51609005 0.56 −3.71 PROTEIN DOWNREG. TU_0055238_0 chr18:2561572-2605627 0.59 −3.71 PROTEIN DOWNREG. TU_0085908_0 chr5:78401241-78420780 0.52 −3.72 ncRNA DOWNREG. TU_0111315_0 chr15:61676589-61681634 0.55 −3.72 PROTEIN DOWNREG. TU_0111311_0 chr15:61676589-61681634 0.55 −3.72 PROTEIN DOWNREG. TU_0023241_0 chr19:40856254-40861198 0.41 −3.72 PROTEIN DOWNREG. TU_0068139_0 chr8:199127296-199147465 0.42 −3.72 ncRNA DOWNREG. TU_0102684_0 chr9:70336502-70344481 0.56 −3.73 PROTEIN DOWNREG. TU_0068764_0 chr1:207854842-207892483 0.49 −3.73 PROTEIN DOWNREG. TU_0053636_0 chr18:55846971-55853340 0.58 −3.74 PROTEIN DOWNREG. TU_0084025_0 chr5:6501949-6545706 0.54 −3.74 NOVEL DOWNREG. TU_0032151_0 chr14:22508055-22508830 0.58 −3.74 PROTEIN DOWNREG. TU_0014650_0 chr17:6295379-6305574 0.62 −3.74 PROTEIN DOWNREG. TU_0076124_0 chr10:104619299-104651033 0.60 −3.75 PROTEIN DOWNREG. TU_0085198_0 chr5:58300638-58305429 0.60 −3.75 PROTEIN DOWNREG. TU_0102686_0 chr9:70837677-70344573 0.55 −3.76 PROTEIN DOWNREG. TU_0112385_0 chr15:71818130-71831566 0.54 −3.76 PROTEIN DOWNREG. TU_0100875_0 chr21:32705500-32809639 0.61 −3.78 PROTEIN DOWNREG. TU_0085928_0 chr1:151800274-151855449 0.49 −3.78 PROTEIN DOWNREG. TU_0063298_0 chr1:62474433-62474872 0.36 −3.78 PROTEIN DOWNREG. TU_0100861_0 chr21:32604246-32608457 0.62 −3.79 PROTEIN DOWNREG. TU_0101015_0 chr21:35010886-35012375 0.55 −3.79 ncRNA DOWNREG. TU_0081086_0 chrX:133993992-133995935 0.73 −3.79 PROTEIN DOWNREG. TU_0068759_0 chr1:207669209-207672813 0.45 −3.79 NOVEL DOWNREG. TU_0069253_0 chr1:223741202-223745600 0.62 −3.79 PROTEIN DOWNREG. TU_0020150_0 chr19:3877291-3879097 0.52 −3.79 ncRNA DOWNREG. TU_0084059_0 chr5:9599140-9608833 0.50 −3.80 PROTEIN DOWNREG. TU_0016922_0 chr17:38430856-38435173 0.51 −3.80 PROTEIN DOWNREG. TU_0013053_0 chr7:134114695-134205949 0.58 −3.81 PROTEIN DOWNREG. TU_0017406_0 chr17:43458534-43470076 0.58 −3.81 PROTEIN DOWNREG. TU_0014681_0 chr17:6295379-6305877 0.50 −3.81 PROTEIN DOWNREG. TU_0058447_0 chr1:9040090-9052238 0.36 −3.81 PROTEIN DOWNREG. TU_0085624_0 chr18:11872611-11875972 0.64 −3.82 PROTEIN DOWNREG. TU_0003717_0 chr6:43381215-43381963 0.49 −3.82 NOVEL DOWNREG. TU_0016578_0 chr17:35883208-35884855 0.52 −3.82 PROTEIN DOWNREG. TU_0101224_0 chr21:40161189-40223184 0.50 −3.82 PROTEIN DOWNREG. TU_0064871_0 chr1:115391459-115433611 0.59 −3.83 PROTEIN DOWNREG. TU_0097462_0 chr8:37773618-37822041 0.55 −3.85 PROTEIN DOWNREG. TU_0066742_0 chr1:154860755-154862200 0.42 −3.83 PROTEIN DOWNREG. TU_0090638_0 chr11:14242208-14246823 0.55 −3.83 PROTEIN DOWNREG. TU_0046628_0 chr4:3735533-3740037 0.46 −3.83 PROTEIN DOWNREG. TU_0024608_0 chr19:51842692-51911641 0.53 −3.83 PROTEIN DOWNREG. TU_0071146_0 chr20:25381375-25432639 0.58 −3.84 PROTEIN DOWNREG. TU_0080097_0 chr12:55301840-55307803 0.56 −3.85 PROTEIN DOWNREG. TU_0062615_0 chr1:48974664-48997227 0.51 −3.85 PROTEIN DOWNREG. TU_0013669_0 chr7:150272983-150305963 0.52 −3.86 PROTEIN DOWNREG. TU_0102682_0 chr9:70197177-70337519 0.56 −3.86 PROTEIN DOWNREG. TU_0104855_0 chr9:131689287-131691419 0.64 −3.86 PROTEIN DOWNREG. TU_0116336_0 chr2:48677181-48685259 0.65 −3.86 PROTEIN DOWNREG. TU_0116619_0 chr2:60532830-60533546 0.47 −3.87 PROTEIN DOWNREG. TU_0034462_0 chr14:69415893-69568826 0.48 −3.87 PROTEIN DOWNREG. TU_0067213_0 chr1:163086189-163087684 0.59 −3.87 PROTEIN DOWNREG. TU_0066337_0 chr1:148457403-148475119 0.56 −3.87 NOVEL DOWNREG. TU_0062461_0 chr1:46461750-46463004 0.51 −3.88 PROTEIN DOWNREG. TU_0080098_0 chr12:56302807-56307767 0.56 −3.88 PROTEIN DOWNREG. TU_0034421_0 chr14:68410559-68412495 0.62 −3.88 PROTEIN DOWNREG. TU_0016601_0 chr17:36911114-36929728 0.39 −3.88 PROTEIN DOWNREG. TU_0079221_0 chr12:51194638-51200498 0.43 −3.89 PROTEIN DOWNREG. TU_0112752_0 chr15:76184009-76210733 0.55 −3.90 PROTEIN DOWNREG. TU_0028410_0 chrX:48910899-48929704 0.68 −3.91 PROTEIN DOWNREG. TU_0076488_0 chr10:123227854-123347940 0.55 −3.92 NOVEL DOWNREG. TU_0093208_0 chr11:65396933-65397655 0.45 −3.92 PROTEIN DOWNREG. TU_0078229_0 chr12:27016771-27017190 0.47 −3.92 PROTEIN DOWNREG. TU_0064620_0 chr1:111962701-112059304 0.61 −3.92 PROTEIN DOWNREG. TU_0005224_0 chr8:107917248-108088034 0.60 −3.93 PROTEIN DOWNREG. TU_0023668_0 chr19:44114820-44158190 0.56 −3.93 PROTEIN DOWNREG. TU_0041856_0 chr3:190990156-191097717 0.44 −3.93 PROTEIN DOWNREG. TU_0107364_0 chr22:36658502-36671784 0.62 −3.93 PROTEIN DOWNREG. TU_0079224_0 chr12:61194638-61199100 0.43 −3.94 PROTEIN DOWNREG. TU_0027357_0 chrX:17728093-17737982 0.57 −3.94 PROTEIN DOWNREG. TU_0071013_0 chr20:19141491-19652034 0.55 −3.95 PROTEIN DOWNREG. TU_0060281_0 chr1:27204050-27211524 0.48 −3.95 PROTEIN DOWNREG. TU_0096007_0 chr11:119482708-119514087 0.45 −3.95 PROTEIN DOWNREG. TU_0058810_0 chr1:11631006-11637486 0.50 −3.95 ncRNA DOWNREG. TU_0102668_0 chr9:67902293-67904671 0.52 −3.96 PROTEIN DOWNREG. TU_0103226_0 chr9:93524079-93559558 0.55 −3.96 PROTEIN DOWNREG. TU_0098334_0 chr8:68508843-68581618 0.43 −3.96 NOVEL DOWNREG. TU_0084068_0 chr5:9602147-9603383 0.49 −3.96 ncRNA DOWNREG. TU_0018887_0 chr17:73068191-73068655 0.29 −3.97 PROTEIN DOWNREG. TU_0020916_0 chr19:9720305-9727293 0.55 −3.97 PROTEIN DOWNREG. TU_0018819_0 chr7:72184546-72195820 0.59 −3.97 NOVEL DOWNREG. TU_0042081_0 chr3:197374550-197376798 0.46 −3.97 PROTEIN DOWNREG. TU_0065854_0 chr1:149850009-149852298 0.46 −3.98 PROTEIN DOWNREG. TU_0111301_0 chr18:81676588-51684928 0.54 −3.98 PROTEIN DOWNREG. TU_0073443_0 chr10:5556713-3558609 0.43 −3.99 PROTEIN DOWNREG. TU_0030581_0 chrX:118096546-118104692 0.38 −3.99 PROTEIN DOWNREG. TU_0019780_0 chr

: 120

-120

0.55 −4.00 PROTEIN DOWNREG. TU_0081660_0 chr12: 108705678-108718771 0.50−4.00 PROTEIN DOWNREG. TU_0046397_0 chr4: 2932589-2050090 0.46 −4.00PROTEIN DOWNREG. TU_0122440_0 chr2: 219991398-219999705 0.53 −4.01PROTEIN DOWNREG. TU_0011534_0 chr7: 99085437-99096154 0.36 −4.01 PROTEINDOWNREG. TU_0047205_0 chr4: 37815997-37817290 0.59 −4.02 PROTEINDOWNREG. TU_0017005_0 chr17: 39308253-39337366 0.52 −4.02 PROTEINDOWNREG. TU_0052436_0 chr16: 15704459-15858435 0.54 −4.03 PROTEINDOWNREG. TU_0014762_0 chr17: 7128572-7131411 0.46 −4.03 PROTEIN DOWNREG.TU_0080075_0 chr12: 56290183-56301803 0.53 −4.03 PROTEIN DOWNREG.TU_0083295_0 chr5: 177597111-177621358 0.48 −4.03 PROTEIN DOWNREG.TU_0062594_0 chr16: 19775320-19780719 0.68 −4.03 PROTEIN DOWNREG.TU_0068168_0 chr1: 199700556-199742901 0.61 −4.04 ncRNA DOWNREG.TU_0102657_0 chr9: 67902293-67908869 0.54 −4.04 PROTEIN DOWNREG.TU_0088729_0 chr8: 43825496-43526789 0.55 −4.04 PROTEIN DOWNREG.TU_0071246_0 chr20: 29913077-29921837 0.42 −4.05 NOVEL DOWNREG.TU_0050224_0 chr4: 147115887-147190781 0.25 −4.06 PROTEIN DOWNREG.TU_0110166_0 chr15: 48172154-43198892 0.49 −4.07 PROTEIN DOWNREG.TU_0030085_0 chrX: 101782933-101800062 0.56 −4.07 PROTEIN DOWNREG.TU_0021042_0 chr19: 10435466-10441506 0.61 −4.08 PROTEIN DOWNREG.TU_0097463_0 chr8: 37812227-37826549 0.58 −4.08 PROTEIN DOWNREG.TU_0101682_0 chr9: 734412-736069 0.67 −4.08 PROTEIN DOWNREG.TU_0030157_0 chrX: 102750729-102751737 0.44 −4.09 NOVEL DOWNREG.TU_0098190_0 chr8: 61704765-61708199 0.40 −4.09 PROTEIN DOWNREG.TU_0082947_0 chr1: 53744955-53838542 0.42 −4.09 PROTEIN DOWNREG.TU_0078008_0 chr12: 21679541-21762042 0.57 −4.09 PROTEIN DOWNREG.TU_0017582_0 chr17: 45858594-45907395 0.54 −4.09 PROTEIN DOWNREG.TU_0080022_0 chr6: 1555144-1659122 0.53 −4.09 PROTEIN DOWNREG.TU_0031424_0 chrX: 149482223-149433104 0.47 −4.10 PROTEIN DOWNREG.TU_0065603_0 chr1: 149275738-149286201 0.42 −4.10 PROTEIN DOWNREG.TU_0037859_0 chr3: 45240966-45242817 0.49 −4.11 PROTEIN DOWNREG.TU_0162271_0 chr9: 34511045-34512853 0.50 −4.11 PROTEIN DOWNREG.TU_0035605_0 chr14: 95254401-93273368 0.49 −4.11 PROTEIN DOWNREG.TU_0064621_0 chr1: 112047963-1120

0.54 −4.11 ncRNA DOWNREG. TU_0031098_0 chrX: 134057388-134058604 0.47−4.11 PROTEIN DOWNREG. TU_0018799_0 chr17: 72061371-72080938 0.61 −4.11PROTEIN DOWNREG. TU_0011129_0 chr7: 94135058-94136943 0.41 −4.11 NOVELDOWNREG. TU_0036396_0 chr14: 104617328-104619095 0.41 −4.12 PROTEINDOWNREG. TU_0056255_0 chr5: 92944260-92956054 0.57 −4.12 ncRNA DOWNREG.TU_0074501_0 chr10: 60429298-60431031 0.42 −4.12 PROTEIN DOWNREG.TU_0073757_0 chr10: 17672347-17899481 0.56 −4.13 PROTEIN DOWNREG.TU_0015457_0 chr17: 195

1898-19287156 0.45 −4.13 PROTEIN DOWNREG. TU_0122402_0 chr2:219821926-219824741 0.61 −4.13 PROTEIN DOWNREG. TU_0116618_0 chr2:60932830-60633902 0.49 −4.13 PROTEIN DOWNREG. TU_0029963_0 chrX:100220537-100238065 0.51 −4.15 PROTEIN DOWNREG. TU_0028949_0 chrK:64964077-64878513 0.61 −4.15 PROTEIN DOWNREG. TU_0082443_0 chr5:154178336-164210363 0.57 −4.16 PROTEIN DOWNREG. TU_0107372_0 chr22:36668731-36871784 0.56 −4.17 PROTEIN DOWNREG. TU_0016330_0 chr17:38070936-35071660 0.57 −4.17 PROTEIN DOWNREG. TU_0016596_0 chr17:36923524-36946925 0.58 −4.17 PROTEIN DOWNREG. TU_0014764_0 chr17:7131441-7134452 0.45 −4.18 PROTEIN DOWNREG. TU_0070473_0 chr20:2621571-2702522 0.60 −4.18 PROTEIN DOWNREG. TU_0053602_0 chr1:149282296-149268718 0.40 −4.19 PROTEIN DOWNREG. TU_0105435_0 chr9:138997874-138999099 0.37 −4.19 PROTEIN DOWNREG. TU_0015445_0 chr17:19415396-19422513 0.46 −4.20 PROTEIN DOWNREG. TU_0013012_0 chr17:74597027-74930278 0.42 −4.21 PROTEIN DOWNREG. TU_0048538_0 chr4:21336928-81344460 0.41 −4.22 PROTEIN DOWNREG. TU_0098385_0 chr8:68508843-68509222 0.41 −4.22 PROTEIN DOWNREG. TU_0076499_0 chr10:225227854-123248042 0.53 −4.23 PROTEIN DOWNREG. TU_0117482_0 chr2:73973697-71000287 0.56 −4.23 PROTEIN DOWNREG. TU_0114778_0 chr2:20264034-20288661 0.45 −4.24 PROTEIN DOWNREG. TU_0016318_0 chr17:33917848-33935788 0.53 −4.25 PROTEIN DOWNREG. TU_0071893_0 chr20:34603301-34611746 0.59 −4.25 PROTEIN DOWNREG. TU_0073523_0 chr10:8136827-8157157 0.44 −4.26 PROTEIN DOWNREG. TU_0064500_0 chr1:110861354-110079791 0.42 −4.27 PROTEIN DOWNREG. TU_0064862_0 chr1: 149

50009-149952444 0.41 −4.27 PROTEIN DOWNREG. TU_0030064_0 chrX:101268429-101269091 0.44 −4.28 PROTEIN DOWNREG. TU_0060278_0 chr1:27192773-27200190 0.51 −4.28 PROTEIN DOWNREG. TU_0000013_0 chr6:1287191-1259372 0.36 −4.29 PROTEIN DOWNREG. TU_0120707_0 chr2:17686568-176869190 0.45 −4.31 PROTEIN DOWNREG. TU_0016744_0 chr17:37790358-37809206 0.54 −4.31 PROTEIN DOWNREG. TU_0016827_0 chr17:38085330-38071660 0.53 −4.31 PROTEIN DOWNREG. TU_0056190_0 chr18:26824024-26842486 0.43 −4.33 PROTEIN DOWNREG. TU_0096964_0 chr8:22027917-22043914 0.47 −4.35 PROTEIN DOWNREG. TU_0030062_0 chrX:101267701-101269091 0.41 −4.35 ncRNA DOWNREG. TU_0120713_0 chr2:176930391-176969560 0.49 −4.35 PROTEIN DOWNREG. TU_0011537_0 chr7:99589728-99111736 0.39 −4.39 PROTEIN DOWNREG. TU_0107366_0 chr22:36038731-36673469 0.54 −4.39 PROTEIN DOWNREG. TU_0065341_0 chr1:148496851-148500610 0.35 −4.39 PROTEIN DOWNREG. TU_0013076_0 chr17:12510065-12612990 0.50 −4.40 PROTEIN DOWNREG. TU_0087752_0 chr5:199206352-199211418 0.44 −4.40 PROTEIN DOWNREG. TU_0108990_0 chr15:34970176-35180015 0.51 −4.41 PROTEIN DOWNREG. TU_0062566_0 chr1:47037330-47057598 0.43 −4.42 PROTEIN DOWNREG. TU_0018825_0 chr17:2192513-2192794 0.47 −4.43 PROTEIN DOWNREG. TU_0002566_0 chr6:55797424-55798978 0.37 −4.44 PROTEIN DOWNREG. TU_0074074_0 chr10:29814868-29815135 0.26 −4.44 PROTEIN DOWNREG. TU_0110179_0 chr15:45196205-45255205 0.43 −4.46 PROTEIN DOWNREG. TU_0082372_0 chr12:116130336-116130610 0.41 −4.47 ncRNA DOWNREG. TU_0102658_0 chr9:67902293-67908683 0.46 −4.48 PROTEIN DOWNREG. TU_0024160_0 chr19:48777171-48778386 0.51 −4.49 PROTEIN DOWNREG. TU_0031081_0 chrX:133993992-134013925 0.64 −4.49 PROTEIN DOWNREG. TU_0015447_0 chr17:19421649-19423000 0.46 −4.50 PROTEIN DOWNREG. TU_0016834_0 chr17:38072130-38072515 0.54 −4.50 PROTEIN DOWNREG. TU_0120709_0 chr2:176677352-176697902 0.49 −4.50 PROTEIN DOWNREG. TU_0041205_0 chr3:171619688-171634575 0.48 −4.53 PROTEIN DOWNREG. TU_0110178_0 chr15:43196270-43241274 0.43 −4.54 PROTEIN DOWNREG. TU_0084473_0 chr1:110000292-110079791 0.51 −4.58 ncRNA DOWNREG. TU_0120715_0 chr2:176692475-176697902 0.50 −4.58 PROTEIN DOWNREG. TU_0110180_0 chr15:43196205-43243358 0.43 −4.63 PROTEIN DOWNREG. TU_0024922_0 chr19:54255568-54259943 0.42 −4.64 ncRNA DOWNREG. TU_0119818_0 chr2:38109039-38116939 0.32 −4.64 ncRNA DOWNREG. TU_0067289_0 chr1:166307141-166318970 0.48 −4.69 NOVEL DOWNREG. TU_0095765_0 chr11:117640504-117642734 0.36 −4.69 PROTEIN DOWNREG. TU_0058445_0 chr1:9017797-9040122 0.33 −4.70 PROTEIN DOWNREG. TU_0047068_0 chr4:23402764-23403824 0.41 −4.72 PROTEIN DOWNREG. TU_0018882_0 chr17:38260060-38263683 0.51 −4.82 NOVEL DOWNREG. TU_0098382_0 chr8:68494189-68495887 0.23 −4.83 PROTEIN DOWNREG. TU_0110177_0 chr15:43196768-43245735 0.47 −4.86 PROTEIN DOWNREG. TU_0089598_0 chr11:303980-310982 0.35 −4.87 PROTEIN DOWNREG. TU_0107527_0 chr22:37740155-37746215 0.44 −4.88 PROTEIN DOWNREG. TU_0107528_0 chr22:37741248-37746215 0.43 −4.90 PROTEIN DOWNREG. TU_0032311_0 chr14:23612588-23617134 0.32 −5.04

indicates data missing or illegible when filed

TABLE 5 Fold change Expected score Observed (PCA vs q-value PCAT ID GeneChromosomal Location (dExp) score (d) Benign (%) PCAT-1 TU_0099866_0chr8: 128087842-128095202 −2.2654014 5.444088 6.9071784 0 PCAT-2TU_0090142_0 chr11: 4745677-4760303 −2.4408573 4.6781354 11.39658 0PCAT-3 TU_0054605_0 chr16: 82380336-82394836 −2.1786723 4.46124555.8916535 0 PCAT-4 TU_0090140_0 chr11: 4748163-4759145 −2.1153826 4.43457.1933164 0 PCAT-5 TU_0078286_0 chr12: 2393286-32405731 −1.91642194.312603 3.5655262 0 PCAT-6 TU_0090864_0 chr6: 128084589-128103681−1.7214081 4.265536 3.8937242 0 PCAT-7 TU_0084308_0 chr5:15938756-15949124 −1.9636476 4.124071 4.747601 0 PCAT-8 TU_0084303_0chr6: 15899476-15955226 −2.0245786 4.0520086 7.1035067 0 PCAT-9TU_0082746_0 chr12: 120197102-120197416 −1.861408 3.7551165 5.1431665 0PCAT-10 TU_0078296_0 chr12: 32394534-32405549 −1.5944241 3.69029143.034359 0 PCAT-11 TU_0078290_0 chr12: 32394534-32410898 −1.53379543.675318 3.1572607 0 PCAT-12 TU_0002597_0 chr12: 32394534-32410898−1.6263148 3.6469774 3.352418 0 PCAT-13 TU_0049368_0 chr6:34335202-34338521 −1.6894234 3.6079373 2.8299546 0 PCAT-14 TU_0106548_0chr4: 106772318-106772770 −1.939075 3.591398 5.3962547 0 PCAT-15TU_0078293_0 chr22: 22209111-22212055 −1.5212961 3.5705945 2.9213174 0PCAT-16 TU_0099834_0 chr8: 128301495-128307576 −1.4445064 3.56586432.516981 0 PCAT-17 TU_0112014_0 chr15: 67722165-67739990 −1.63262953.562463 3.694224 0 PCAT-18 TU_0084306_0 chr5: 15896315-15947086 −1.8453.5603588 5.746707 0 PCAT-19 TU_0124240_0 chr2: 1534883-1538193−1.6870209 3.5233572 4.339847 0 PCAT-20 TU_0008439_0 chr7:24236191-24236455 −1.6302066 3.5071697 6.6821446 0 PCAT-21 TU_0078299_0chr12: 32200296-32292169 −1.7297353 3.606232 3.2923664 0 PCAT-22TU_0000033_0 chr6: 1619606-1668581 −1.7680657 3.434185 2.2470813 0PCAT-23 TU_0096472_0 chr11: 133844590-133862924 −1.8782617 3.4103565.9854193 0 PCAT-24 TU_0114259_0 chr2: 1686782-1687314 −1.66623773.3919659 5.080926 0 PCAT-25 TU_0096473_0 chr11: 133844500-133862995−1.8963361 3.859823 6.1071715 0 PCAT-26 TU_0100362_0 chr8:144914456-144930753 −1.6521469 3.3805158 3.8420231 0 PCAT-27TU_0040394_0 chr3: 135418632-133441252 −1.6208396 3.3201025 2.8724674 0PCAT-28 TU_0043432_0 chr13: 34062994-34056503 −1.6739871 3.20375513.2093527 0 PCAT-29 TU_0112020_0 chr15: 67764259-67801825 −1.56033163.1967351 3.593551 0 PCAT-30 TU_0042717_0 chr13: 23149908-23200198−1.0654948 3.1685438 4.9633407 0 PCAT-31 TU_0078232_0 chr12:62290485-62406307 −1.4503008 3.151879 2.8011364 0 PCAT-32 TU_0084146_0chr5: 14025126-14062770 −1.6452767 3.1257985 2.6193055 0 PCAT-33TU_0066168_0 chr18: 22477042-22477666 −1.5381516 3.0557241 3.1951044 0PCAT-34 TU_0040383_0 chr3: 133360941-133429262 −1.5558791 3.04165083.7478442 0 PCAT-35 TU_0112025_0 chr15: 67780574-87782345 −1.68159773.0412362 3.433415 0 PCAT-36 TU_0041688_0 chr3: 186743298-186741933−1.4748297 3.0062308 2.543468 0 PCAT-37 TU_0103642_0 chr9:109187089-109187455 −1.7387192 2.998958 6.6124363 0 PCAT-38 TU_0040375_0chr3: 133280694-133394609 −1.5469999 2.9753568 3.9068055 0 PCAT-39TU_0047312_0 chr4: 19217689-39222163 −1.6388936 2.9124916 3.6121209 0PCAT-40 TU_0106545_0 chr22: 22218478-22219162 −1.7586407 2.8898563.7357745 0 PCAT-41 TU_0054541_0 chr16: 79408800-79435066 −1.74859342.8699164 6.647557 0 PCAT-42 TU_0060446_0 chr1: 28438629-28450156−1.4880521 2.857332 1.0824111 0 PCAT-43 TU_0072907_0 chr20:55759486-55771563 −1.5254781 2.7966201 2.812179 0 PCAT-44 TU_0043453_0chr13: 33844637-33845921 −1.5793877 2.7919009 3.6403422 0 PCAT-45TU_0038678_0 chr3: 53515951-53517078 −1.7047809 2.7858517 3.6909987 0PCAT-46 TU_0101786_0 chr9: 3408690-3415374 −1.4780945 2.78220993.3066912 0 PCAT-47 TU_0101709_0 chr9: 3411967-3415374 −1.48523732.7622206 3.1886175 0 PCAT-48 TU_0166544_0 chr22: 22210421-22220506−1.6153399 2.7578155 3.7418716 0 PCAT-49 TU_0046121_0 chr4:766363-766599 −1.5697786 2.7573307 1.485532 0 PCAT-50 TU_0106542_0chr22: 22211315-22220506 −1.6098742 2.755221 3.3781004 0 PCAT-51TU_0106541_0 chr22: 22209111-22219162 −1.6593723 2.7341027 3.664146 0PCAT-52 TU_0044453_0 chr13: 51505777-51524522 −1.3416 2.732019 2.5369530 PCAT-53 TU_0104717_0 chr9: 130697833-130698832 −1.2938 2.72197322.3344588 0 PCAT-54 TU_0039014_0 chr5: 176014905-176015351 −1.39678732.7047258 3.7803582 0 PCAT-55 TU_0168452_0 chr15: 19344745-19362916−1.5839852 2.6759455 1.8484153 0 PCAT-56 TU_0112053_0 chr15:67645590-67775246 −1.4386703 2.668052 3.045022 0 PCAT-57 TU_0078286_0chr12: 32395588-32405731 −1.3580605 2.6660874 2.6121044 0 PCAT-58TU_0078303_0 chr12: 32274210-32274530 −1.5020599 2.65856 3.3306372 0PCAT-59 TU_0112054_0 chr15: 67644390-67650387 −1.5175762 2.85098882.9933636 0 PCAT-60 TU_0071087_0 chr20: 21428679-21429454 −1.49166882.649109 4.6481714 0 PCAT-61 TU_0072906_0 chr20: 95759768-55770657−1.5059631 2.645004 2.95756 0 PCAT-62 TU_0054240_0 chr16:70155175-70173873 −1.4715649 2.6437716 3.5309577 0 PCAT-63 TU_0047330_0chr4: 39217641-39222163 −1.5139307 2.6277235 3.0695639 0 PCAT-64TU_0055435_0 chr18: 6715938-6719172 −1.6048826 2.6173768 2.9221427 0PCAT-65 TU_0079791_0 chr12: 54971063-54971481 −1.4415668 2.60108232.0141602 0 PCAT-66 TU_0043411_0 chr13: 33918267-33926769 −1.4950642.5991623 3.3860362 0 PCAT-67 TU_0056121_0 chr18: 20196762-20197522−1.2526748 2.5938754 1.7191441 0 PCAT-68 TU_0043412_0 chr13:33918267-33935946 −1.5891836 2.5901399 4.2804045 0 PCAT-69 TU_0065837_0chr1: 149791252-149795934 −1.3852053 2.5882297 2.9343975 0 PCAT-70TU_0043461_0 chr13: 33825711-33845275 −1.5994886 2.5853698 4.3461533 0PCAT-71 TU_0006453_0 chr6: 144659813-144660143 −1.4985942 2.57441072.2007995 0 PCAT-72 TU_0048596_0 chr4: 30329017-80348259 −1.57443822.5690413 2.8022916 0 PCAT-73 TU_0084140_0 chr5: 14003669-14054874−1.4040573 2.5472755 2.5979325 0 PCAT-74 TU_0082982_0 chr12:121776584-121777370 −1.5293782 2.5458217 2.6197503 0 PCAT-75TU_0013212_0 chr7: 13890883-139001515 −1.2298403 2.544434 1.6879753 0PCAT-76 TU_0072912_0 chr20: 55779532-55780817 −1.4302964 2.54067373.2653345 0 PCAT-77 TU_0112281_0 chr15: 70586704-70590792 −1.45901552.5875097 2.4288568 0 PCAT-78 TU_0048787_0 chr4: 88120068-88124880−1.3735119 2.5328946 2.233808 0 PCAT-79 TU_0108455_0 chr15:19358626-19365341 −1.6651321 2.5261333 1.9462687 0 PCAT-80 TU_0091997_0chr11: 58560356-58573012 −1.3149038 2.5185204 2.1176686 0 PCAT-81TU_0122655_0 chr2: 202985284-202998634 −1.4014161 2.476237 2.21941880.859614 PCAT-82 TU_0071798_0 chr20: 33775260-33778511 −1.33886652.4848917 1.65688733 0.850371 PCAT-83 TU_0049200_0 chr4:102469973-102476087 −1.3222212 2.456723 1.9456172 0.841324 PCAT-84TU_0121714_0 chr2: 203295212-203314865 −1.3457565 2.4496663 1.76242740.832468 PCAT-85 TU_0098937_0 chr2: 95748751-95751821 −1.4532137 2.422482.2326834 0.823797 PCAT-86 TU_0108453_0 chr15: 19356996-19364013−1.8033699 2.4094539 3.839975 0.767811 PCAT-87 TU_0114170_0 chr15:99659312-99669199 −1.4358851 2.4062114 2.1252658 0.768711 PCAT-88TU_0089906_0 chr11: 1042845-1045705 −1.3899238 2.401665 2.839095.50.767811 PCAT-89 TU_0001559_0 chr6: 30283700-30286011 −1.35170652.3987799 1.5110766 0.767811 PCAT-90 TU_0050557_0 chr4:159976338-160016453 −1.17525 2.398688 2.0524442 0.767811 PCAT-91TU_0078294_0 chr12: 32395632-32413084 −1.4560982 2.3969867 2.18632080.767811 PCAT-92 TU_0044933_0 chr13: 94755992-94760688 −1.29051972.3965187 2.189938 0.767811 PCAT-93 TU_0017730_0 chr17:52346638-52346880 −1.4169512 2.3874857 1.4708191 0.760428 PCAT-94TU_0039020_0 chr3: 66578629-66507777 −1.2662895 2.3720088 1.71127080.712473 PCAT-95 TU_0049213_0 chr4: 102461960-102476087 −1.27251392.3871806 1.8878821 0.712473 PCAT-96 TU_0093070_0 chr11:64945809-64961189 −1.2954472 2.3645105 1.9128969 0.712473 PCAT-97TU_0051063_0 chr4: 187244297-187244767 1.8922851 −2.8485844 0.509831550.732264 PCAT-98 TU_0098190_0 chr8: 61704765-61708199 1.9825526−2.8612607 0.4027831 0.732264 PCAT-99 TU_0038811_0 chr3:57890130-57890884 1.9820296 −2.8837616 0.44431657 0.732264 PCAT-100TU_0020814_0 chr19: 9718812-9721799 1.8433232 −2.9248087 0.506230060.732264 PCAT-101 TU_0112056_0 chr15: 89658838-69678409 1.837821−3.0355222 0.48161976 0 PCAT-102 TU_0056396_0 chr14: 104617328-1046190951.549786 −3.1192882 0.45514825 0 PCAT-103 TU_0095765_0 chr11:117640504-117642734 2.1002219 −3.2632742 0.38160667 0 PCAT-104TU_0050224_0 chr4: 147115887-147190781 2.1981242 −3.2975357 0.28569755 0PCAT-105 TU_0112089_0 chr15: 69667695-60691724 1.8148681 −3.38166260.43567468 0 PCAT-106 TU_0098382_0 chr8: 68494189-68495887 2.5433978−4.0586042 0.30793378 0

TABLE 6 Median Maximum Expression Expression PCAT ID Gene ChromosomalLocation Outlier Score (RPKM) (RPKM) PCAT-107 TU_0029004_0 chrX:66691350-56692032 130.7343145 1 90.921 PCAT-108 TU_0054542_0 chr16:79420131-79423590 227.0430857 5.60998 135.85 PCAT-109 TU_0120899_0 chr2:180689090-180696402 223.5416436 1.0525222 94.6932 PCAT-110 TU_0054540_0chr16: 79419351-79423673 119.050847 4.161985 94.4461 PCAT-111TU_0120918_0 chr2: 181297540-181400892 112.710111 1.4533705 92.1795PCAT-112 TU_0054538_0 chr16: 79408946-79450819 93.01851659 1.83034393.1207 PCAT-113 TU_0059541_0 chr2: 20685471-20686432 68.35725071.783109 1375.15 PCAT-114 TU_0120524_0 chr2: 181331111-18142748563.95455962 1.3891845 365.202 PCAT-115 TU_0074308_0 chr10:42652247-42653596 60.91841567 1.393607 65.7712 PCAT-116 TU_0049192_0chr4: 102257900-102306678 59.24997694 1.3854525 69.2423 PCAT-117TU_0054537_0 chr16: 79406933-79430041 53.04481877 1.8534395 42.751PCAT-118 TU_0120900_0 chr2: 180916864-180985957 55.8438747 1 67.6582PCAT-119 TU_0114527_0 chr2: 10858318-10858530 54.76455104 1.296977535.0059 PCAT-120 TU_0120923_0 chr2: 181328093-181419226 52.97832271.2821 232.556 PCAT-121 TU_0049231_0 chr4: 102257900-10225969552.77001947 1.34042 67.6276

TABLE 7 Median Maximum Outlier Expression Expression Rank GeneChromosomal location Score (RPKM) (RPKM) 1 CRISP3 chr6:49803053-49813070 294.56446 1.5414775 478.812 2 SPINK1 chr5:147184335-147191453 177.19518 2.484455 624.733 3 TU_0029004_0 chrX:66691350-66692032 130.73491 1 90.921 4 TU_0054542_0 chr16:79420131-79423590 127.0431 5.60998 135.85 5 TU_0120899_0 chr2:180689090-180696402 123.54164 1.0525222 94.6932 6 ERG chr21:38673821-38792298 119.446 3.421615 178.826 7 TU_0054540_0 chr16:79419351-79423673 119.09085 4.161985 94.4461 8 ERG chr21:38673821-38792298 117.60294 3.470755 176.186 9 ERG chr21:38673821-38955574 117.26408 3.385695 170.663 10 ERG chr21:38673821-38955574 116.33448 3.40077 170.443 11 TU_0120918_0 chr2:181297540-181400892 112.71011 1.4533705 92.1795 12 C7orf68 chr7:127883119-127885708 105.18504 6.835525 336.148 13 CSRP3 chr11:19160153-19180106 101.12947 1 148.45 14 C7orf68 chr7:127883119-127885708 100.63202 7.08303 337.76 15 COL2A1 chr12:46653014-46684552 99.166329 1.2285615 96.0977 16 C1orf64 chr1:16203317-16205771 98.085922 3.62012 252.013 17 TU_0054538_0 chr16:79403946-79450819 98.018517 1.830343 93.1207 18 COL2A1 chr12:46653014-46684552 97.347905 1.2416035 94.6672 19 CSRP3 chr11:19160153-19180165 96.730187 1 141.963 20 COL9A2 chr1: 40538749-4055552674.408443 19.24815 570.961 21 PLA2G7 chr6: 46780012-46811389 69.52117510.83567 97.8331 22 AGT chr1: 228904891-228916959 69.319886 4.797365189.281 23 TU_0059541_0 chr1: 20685471-20686432 68.357251 1.7831091375.15 24 ETV1 chr7: 13897382-13992664 68.218569 1.932797 138.519 25ETV1 chr7: 13897382-13992664 67.723331 1.9899945 142.406 26 ETV1 chr7:13897382-13992664 67.680571 1.9915925 143.632 27 PLA2G7 chr6:46780011-46811110 67.089039 10.62 95.3551 28 ETV1 chr7:13897382-13997390 66.381191 2.097225 143.975 29 ETV1 chr7:13897382-13997575 65.563724 2.074935 141.069 30 MUC6 chr11:1002823-1026706 64.7328 1.466194 351.862 31 TU_0120924_0 chr2:181331111-181427485 63.95456 1.3891845 365.202 32 ETV1 chr7:13897382-13996167 63.929225 2.05648 135.131 33 ETV1 chr7:13897382-13996167 62.424072 2.03086 131.644 34 TU_0074308_0 chr10:42652247-42653596 60.918416 1.393607 65.7712 35 TU_0049192_0 chr4:102257900-102306678 59.249977 1.3854525 69.2423 36 TU_0054537_0 chr16:79406933-79430041 58.04482 1.8534395 42.751 37 RGL3 chr19:11365731-11391018 57.528689 7.660035 91.2238 38 RGL3 chr19:11365731-11391018 57.393056 7.6327 90.6937 39 TMEM458 chr11:129190950-129235108 55.887845 4.87695 60.0414 40 TU_0120900_0 chr2:180926364-180935967 55.843875 1 67.6582 41 PTK6 chr20: 61630219-6163915155.101291 3.420545 114.116 42 TU_0114527_0 chr2: 10858318-1085853054.764551 1.2969775 35.0059 43 TU_0112020_0 chr15: 67764259-6780182553.832769 2.0281615 88.99 44 TU_0120923_0 chr2: 181328093-18141922652.979323 1.2821 232.556 45 TU_0049231_0 chr4: 102257900-10225969552.770019 1.34042 67.6276 46 MON1B chr16: 75782336-75791044 51.71702726.00355 187.807 47 TU_0054541_0 chr16: 79408800-79435066 50.4452481.7164375 32.5832 48 TU_0087466_0 chr5: 136779809-136798173 50.2851691.2738505 42.0309 49 DLX1 chr2: 172658453-172662647 50.043039 2.08862543.0035 50 TU_0108209_0 chr22: 46493579-46531245 47.753833 1.049141926.6643 51 DLX1 chr2: 172658453-172662647 47.159314 1.9682735 38.4705 52SMC4 chr3: 161600123-161635435 47.127047 4.581655 63.2353 53 SMC4 chr3:161601040-161635435 46.967013 4.442065 61.2756 54 TU_0102399_0 chr9:35759438-35761676 46.664973 6.44675 179.711 55 TU_0029005_0 chrX:66690414-66704178 46.155567 1.0870047 38.3022 56 C15orf48 chr15:43510054-43512939 45.732195 19.02125 223.42 57 C15orf48 chr15:43510054-43512339 45.549287 21.28355 248.097 58 EFNA3 chr1:153317971-153326638 44.993943 3.68358 70.5016 59 TU_0043412_0 chr13:33918267-33935946 44.506741 1.311142 15.1968 60 TU_0069093_0 chr1:220878648-220886461 42.645673 1.443496 160.898 61 UGT1A6 chr2:234265059-234346684 42.500058 1.937622 45.753 62 TU_0057051_0 chr18:54524352-54598419 42.108622 2.418785 56.0712 63 AMH chr19:2200112-2203072 41.744334 2.16026 91.244 64 TU_0120908_0 chr2:181147971-181168431 41.650097 1.0750564 48.7957 65 TU_0099873_0 chr8:128138926-128140075 41.420293 1.51101 38.7353 66 HN1 chr17:70642938-70662369 40.495209 16.35625 110.208 67 TU_0022570_0 chr19:20341299-20343938 39.984803 2.912835 98.5739 68 TU_0098937_0 chr8:95748751-95751321 39.740546 1.4422495 51.5935 69 TU_0040375_0 chr3:133280694-133394609 39.664781 2.149005 90.9787 70 HN1 chr17:70642938-70662370 39.655603 16.34725 109.587 71 TU_0120929_0 chr2:181328093-181423017 39.419483 1.2116475 189.765 72 TU_0112004_0 chr15:67644390-67650387 39.300923 6.10665 76.723 73 TU_0108439_0 chr15:19293567-19296333 39.131646 1 27.7534 74 HN1 chr17: 70642938-7066236939.00893 15.53595 103.782 75 SULT1C2 chr2: 108271526-108292803 39.0070621.2259165 91.5617 76 STX19 chr3: 95215904-95230144 38.954223 4.52125546.0375 77 TU_0030420_0 chrX: 112642982-112685485 38.715477 1.089078562.9419 78 TU_0099875_0 chr8: 128138047-128140075 38.489447 1.39341335.8984 79 IJBE2T chr1: 200567406-200577717 38.387515 3.070345 85.973880 SULT1C2 chr2: 108271526-108292803 37.817555 1.215033 88.0858 81TU_0049429_0 chr4: 109263508-109272353 37.794245 1.09915225 29.1838 82STMN1 chr1: 26099193-26105955 37.319869 14.3784 187.062 83 UGT1A1 chr2:234333657-234346684 37.267194 1.660554 35.9476 84 LRRN1 chr3:3816120-3864387 37.229013 3.8912 137.117 85 TU_0886631_0 chr5:113806149-113806936 36.896806 1.0501165 29.6561 86 ORM2 chr9:116131889-116135357 36.878688 3.614505 120.139 87 TU_0084060_0 chr5:7932238-7932523 36.807599 1 23.1979 88 TU_0098644_0 chr8:81204784-81207034 36.779294 1.6013735 64.9663 89 ACSM1 chr16:20542059-20610079 36.280896 13.3707 317.077 90 STMN1 chr1:26099193-26105231 35.882914 12.73275 164.721 91 STMN1 chr1:26099193-26105580 35.823453 14.31935 185.329 92 TU_0120914_0 chr2:181265370-181266053 35.551458 1.053468 30.7074 93 UGT1A7 chr2:234255322-234346684 35.073998 1.667349 33.4378 94 TU_0087462_0 chr5:136386339-136403134 34.992335 1.4450115 27.1703 95 UGT1A3 chr2:234302511-234346684 34.952247 1.6889365 33.4202 96 UGT1A5 chr2:234286376-234346684 34.950003 1.6639345 33.2718 97 FOXD1 chr5:72777840-72780108 34.875512 1.2373575 10.80944 98 ADM chr11:10283217-10285499 34.855767 11.83635 276.194 99 PPFIA4 chr1:201286933-201314487 34.769924 1.566044 43.9812 100 UGT1A10 chr2:234209861-234346690 34.738527 1.652799 32.7318 101 UGT1A4 chr2:234292176-234346684 34.663597 1.655824 32.9264 102 UGT1A9 chr2:234245282-234346690 34.648086 1.655272 32.852 103 TU_0090142_0 chr11:4748677-4760303 34.517072 1.6226305 51.3411 104 TU_0082746_0 chr12:120197102-120197416 34.499713 2.531095 59.9026 105 UGT1A8 chr2:234191029-234346684 34.433379 1.6498025 32.5849 106 TU_0112207_0 chr15:70278422-70286121 34.308752 10.40266 112.274 107 LOC145837 chr15:67641112-67650833 34.291574 7.59729 74.8194 108 TU_0050712_0 chr4:170217424-170228463 34.23107 1.504313 65.5606 109 TU_0043410_0 chr13:33929484-33944669 34.112491 1.393529 24.8401 110 SNHG1 chr11:62376035-62379936 33.971989 33.74365 270.512 111 MUC1 chr1:153424923-153429324 33.838228 16.3238 664.278 112 MUC1 chr1:153424923-153429324 33.828147 15.8436 644.44 113 TU_0099871_0 chr8:128138047-128143500 33.697285 1.412872 33.2958 114 TU_0040383_0 chr3:133360541-133429262 33.548813 2.553955 85.8384 115 MUC1 chr1:153424923-153429324 33.495501 15.91355 627.622 116 TU_0049202_0 chr4:102257900-102304755 33.391066 1.5555505 39.7522 117 TU_0120913_0 chr2:181254530-181266950 33.188328 1 43.8515 118 B4GALNT4 chr11:359794-372116 33.176248 6.3749 80.9639 119 TU_0100059_0 chr8:141258835-141260573 33.169029 1.3615865 44.8943 120 TOP2A chr17:35798321-35827695 33.132056 1.9725825 34.1032 121 MUC1 chr1:153424923-153429324 33.081326 15.9539 632.042 122 TU_0001265_0 chr6:27081719-27082291 33.045746 1.3381905 100.5401 123 C7orf53 chr7:111908143-111918171 33.024251 2.820945 32.2465 124 SLC45A2 chr5:33980477-34020537 32.952911 2.012104 54.8589 125 TU_0099869_0 chr8:128138047-128225937 32.928048 1.308804 30.4657 126 UGT1A6 chr2:234266250-234346690 32.918772 1.662221 31.4671 127 TU_0120917_0 chr2:181265370-181266950 32.796137 1.0771403 36.3557 128 CACNA1D chr3:53504070-53821532 32.608994 4.51306 44.9904 129 UBE2C chr20:43874661-43879003 32.456813 1.6391285 58.398 130 ALDOC chr17:23924259-23928078 32.455953 14.98415 228.812 131 MUC1 chr1:153424923-153429324 32.44845 15.5895 599.062 132 MMP11 chr22:22445035-22456503 32.411555 3.257735 73.9158 133 TU_0084303_0chr5:15899476-15955226 32.39036 2.21168 14.4385 134 CACNA1D chr3:53504070-53821532 32.381439 4.484655 44.6867 135 UBE2C chr20:43874661-43879003 32.358151 1.705223 57.8559 136 CACNA1D chr3:53504070-53821532 32.353332 4.463805 44.2455 137 FGFRL1 chr4:995609-1010686 32.275762 26.0133 450.449 138 FGFRL1 chr4: 996251-101068632.075261 27.0148 468.809 139 FGFRL1 chr4: 995759-1010686 32.06990126.92945 457.246 140 MUC1 chr1: 153424923-153429324 32.011017 15.3218586.058 141 TU_0099922_0 chr8: 128979617-128981414 31.833339 3.3254432.6893 142 TU_0001173_0 chr6: 26385234-26386052 31.823293 2.33959571.3388 143 MUC1 chr1: 153424923-153429324 31.781267 15.22945 587.582144 TMEM178 chr2: 39746141-39798605 31.614406 13.40605 182.08 145 UBE2Cchr20: 43874661-43879003 31.37539 1.7154185 58.1531 146 KCNC2 chr12:73720162-73889778 31.294059 1.8783795 104.225 147 MAGEC2 chrX:141117794-141120742 31.286618 1 34.1099 148 SERHL2 chr22:41279868-41300332 31.131788 3.670135 61.9969 149 KCNC2 chr12:7.3720162-73889778 31.126593 1.868714 108.199 150 GRAMD4 chr22:45401321-45454352 31.063732 5.977725 79.8338

Table 8 shows the number of cancer-associated lncRNAs nominated for fourmajor cancer types. The number validated is indicated in the column onthe right. This table reflects ongoing efforts.

TABLE 8 # of cancer-specific in cRNAs nominated # validated to dateProstate cancer 121 11 Breast cancer 6 6 Lung cancer 36 32 Pancreaticcancer 34 0

Example 2 SchLAP-1 ncRNA Methods Cell Lines

All cell lines were obtained from the American Type Culture Collection(Manassas, Va.). Cell lines were maintained using standard media andconditions. SChLAP-1 or control expressing cell lines were generated bycloning SChLAP-1 or control into the pLenti6 vector (Invitrogen).Stably-transfected RWPE, HME and MCF7 cells were selected usingblasticidin (Invitrogen). For LNCAP and 22Rv1 cells with stableknockdown of SChLAP-1, cells were transfected with SChLAP-1 ornon-targeting shRNA lentiviral constructs for 48 hours. GFP+ cells weredrug-selected using puromycin.

RNA Isolation; cDNA Synthesis; and PCR Experiments

RNA isolation and cDNA synthesis was performed according standardprotocols. Quantitative PCR was performed using Power SYBR GreenMastermix (Applied Biosystems, Foster City, Calif.), using GAPDH andHMBS as housekeeping control genes. The relative quantity of the targetgene was completed for each sample using the ΔΔCt method.

Murine Intracardiac and Subcutaneous In Vivo Models

Intracardiac injection model: 5×10⁵ cells were introduced to CB-17severe combine immunodeficient mice (CB-17 SCID) at 6 weeks of age.Beginning one week post injection, bioluminescent imaging of mice wasperformed weekly using a CCD IVIS system with a 50-mm lens (XenogenCorp.) and the results were analyzed using LivingImage software(Xenogen). Subcutaneous injection model: 1×10⁶ cells were introduced tomice (CB-17 SCID), ages 5-7 weeks, with a matrigel scaffold (BD MatrigelMatrix, BD Biosciences) in the posterior dorsal flank region (n=10 percell line). Tumors were measured weekly using a digital caliper, andendpoint was determined as a tumor volume of 1000 mm³.

Immunoblot Analysis

Cells were lysed in RIPA lysis buffer (Sigma, St. Louis, Mo.)supplemented with HALT protease inhibitor (Fisher). Western blottinganalysis was performed with standard protocols using PolyvinylideneDifluoride membrane (GE Healthcare, Piscataway, N.J.) and the signalsvisualized by enhanced chemiluminescence system as described by themanufacturer (GE Healthcare).

siRNA Knockdown, Proliferation and Invasion Studies

Cells were plated in 100 mM plates at a desired concentration andtransfected with 20 uM experimental siRNA oligos or non-targetingcontrols according to standard protocols. 72 hours post-transfectionwith siRNA, cells were trypsinized, counted with a Coulter counter, anddiluted to 1 million cells/mL. Proliferation assays were performed witha Coulter counter, and invasion of cells through Matrigel (BDBiosciences) was performed according to standard protocols

RNA Immunoprecipitation

RIP assays were performed using a Millipore EZ-Magna RIP RNA-BindingProtein Immunoprecipitation kit (Millipore, #17-701) according to themanufacturer's instructions.

Mayo Clinic Cohort Analyses

Formalin-fixed paraffin embedded (FFPE) samples from 235 prostate cancerpatients from the Mayo Clinic43 were processed for total RNA using theRNeasy FFPE nucleic acid extraction kit (Qiagen). RNA was subjected towhole-transcriptome amplification using the WT-Ovation FFPE system(NuGen, San Carlos, Calif.), biotin-labelled with the Encore BiotinModule (NuGen), and hybridized to Affymetrix Human Exon (HuEx) 1.0 STGeneChips (Affymetrix, Santa Clara Calif.). Microarray data was analyzedas detailed previously (Vergara et al. Front Genet. 3, 23, (2012), andSChLAP-1 expression was determined by Partition Around Medoids (PAM)unsupervised clustering using probe selection region 2518129.

Statistical Analyses for Experimental Studies

All data are presented as means±S.E.M. All experimental assays wereperformed in duplicate or triplicate. Statistical analyses shown infigures represent Fisher's exact tests or two-tailed Student t-tests, asindicated.

Results

RNA-Seq has been used to profile >100 prostate cell lines and tissues,including both localized and metastatic prostate cancers (Prensner, etal. Nat Biotechnol 29, 742-749, (2011)). Given that only a fraction ofprostate cancers present with aggressive clinical features (Cooperberget al., J Clin Oncol 23, 8146-8151 (2005)), cancer outlier profileanalysis (COPA; Tomlins et al., Tomlins, S. A. et al. Recurrent fusionof TMPRSS2 and ETS transcription factor Tomlins et al., Science 310,644-648, science 310 644-648 (2005)) was performed to nominateintergenic lncRNAs selectively upregulated in a subset of cancers.PCAT-109 and PCAT-114 showed striking outlier profiles and ranked amongthe best outliers in prostate cancer when compared to protein-codinggenes (FIG. 40 a). Notably, both are located in a “gene desert” onChromosome 2q31.3, a region with previously unknown ties to prostatecancer (FIG. 40 b and FIG. 43).

Efforts to validate PCAT-109 by PCR and rapid amplification of cDNA ends(RACE) failed, partly due to the fact that this gene is not robustlyexpressed in any prostate cell lines (FIG. 40 b and data not shown). Bycontrast, in the PCAT-114 region, PCR experiments and 5′ and 3′ RACEdefined a 1.4 kb, poly-adenylated gene composed of up to seven exons andspanning nearly 200 kb on Ch2q31.3 (FIG. 40 c and FIG. 44). This genewas named Second Chromosome Locus Associated with Prostate-1 (SChLAP-1)after its genomic location. To further characterize this gene, apublished ChIP-Seq dataset of prostate cancer (Yu et al. Cancer Cell 17,443-454 (2010)) was used and it was found that the transcriptional startsite (TSS) of SChLAP-1 was marked by tri-methylation of H3K4 (H3K4me3)and its gene body harbored tri-methylation of H3K36 (H3K36me3) (FIG. 40c), an epigenetic signature consistent with canonical protein-codinggenes and lncRNAs (Guttman et al., Nature 458, 223-227 (2009)). PCRassays defined numerous splicing isoforms of this gene of which three(termed isoforms #1, #2, and #3, respectively) constituted the vastmajority (>90%) of transcripts in the cell (FIG. 40 d).

Using quantitative PCR (qPCR), it was validated that SChLAP-1 was highlyexpressed in ˜20% of prostate cancers, including metastatic prostatecancer (FIG. 40 e). Moreover, examination of SChLAP-1 expression in anRNA-seq compendium of >600 samples, representing >30 tissue types,demonstrated that SChLAP-1 expression was relatively absent in othertumor types (FIG. 4), demonstrating prostate cancer specific activity.To establish SChLAP-1 as a non-coding gene, three isoforms (isoforms 1,2 and 3) were cloned and in vitro translation assays were performed,which were negative. It was also found that SChLAP-1 expression inprostate cell lines was predominantly located in the nucleus (FIG. 400,while most protein-coding mRNAs are located in the cytoplasm, where theyengage the ribosomal translation machinery.

To elucidate the functional role for SChLAP-1 in prostate cancer, siRNAknockdowns of this gene was performed using two independent siRNAs aswell as siRNA to EZH2, which is essential for cancer cell invasion(Kleer, et al. Proc Natl Acad Sci USA 100, 11606-11611, (2003);Varambally, S. et al. Nature 419, 624-629, (2002)) as a positivecontrol. In three prostate cancer cell lines but not breast and lungcancer cells, knockdown of SChLAP-1 dramatically impaired cell invasionin vitro at a level comparable to EZH2 (FIG. 41 a). SChLAP-1 knockdownalso impaired cell proliferation in prostate cells but not nonprostatecells. To confirm this phenotype, the three most abundant SChLAP-1isoforms were overexpressed in RWPE benign immortalized prostate cellsat physiologic levels similar to the LNCaP cell line. While SChLAP-1overexpression did not impact cell proliferation, RWPE cells expressingall three SChLAP-1 isoforms, but not control cells, exhibited theability to invade through Matrigel model basement membrane matrix invitro (FIG. 41 b). Overexpression of SChLAP-1 in HME benign breast orMCF7 breast cancer cells did not induce cell invasion, consistent withits prostate-specific expression pattern. These data support alineage-specific role for SChLAP-1.

To characterize specific regions of SChLAP-1 essential for its function,deletion constructs tiling every 250 bp were overexpressed in RWPEcells. Deletion of a single 250 bp region (bp 1001-1250 for SChLAP-1isoform #1) shared by all three major isoforms abrogated SChLAP-1mediated invasion in RWPE (FIG. 41 c). In silico modeling with RNAfold22of the SChLAP-1 RNA structure indicated the presence of a RNA hairpin inthis region that is lost specifically in deletion construct #5 (FIG. 41d), implicating this secondary structure in the function of themolecule.

Xenograft analysis of 22Rv1 cells stably knocking down SChLAP-1 furtherconfirmed that this gene is necessary for appropriate cancer cellmetastatic seeding in vivo. To test this, intracardiac injection oftumor cells was performed and luciferase signal from mouse lungs anddistant metastases was monitored. These experiments showed that 22Rv1shSChLAP-1 cells displayed impaired metastatic seeding at both proximal(lungs) and distal sites (FIG. 41 e). 22Rv1 shSChLAP-1 cells displayedboth fewer gross metastatic sites overall (an average 3.66 metastaticsites in shNT mice vs. 2.07 metastatic sites in shSChLAP-1 #1 and 1.07sites in shSChLAP-1 #2 mice, p<0.05, Student's t-test) as well assmaller metastatic tumors when they did form (FIG. 41 f). shSChLAP-1subcutaneous xenografts displayed slower tumor progression in vivo,though this was due to delayed tumor engraftment rather than alteredtumor growth kinetics. Together, these in vitro and in vivo data supporta prostate-specific role for SChLAP-1 in cancer cell invasion,metastasis, and aggressiveness.

To interrogate SChLAP-1 function, microarray profiling of 22Rv1 andLNCaP prostate cancer cells treated with SChLAP-1 or control siRNAs wasperformed, which revealed 165 upregulated and 264 downregulated genes ina highly significant manner (q-value <0.001), indicating that SChLAP-1contributes to the positive and negative regulation of numerous genes.

After ranking genes according to differential expression by SignificanceAnalysis of Microarrays (SAM) (Tusher et al., Proc Natl Acad Sci USA 98,5116-5121, (2001)), Proc Natl Acad Sci USA 102, 15545-15550 (2005)) wasused to search for enrichment across the Molecular Signatures Database(MSigDB) (Liberzon, A. et al. Bioinformatics 27, 1739-1740, (2011)).Among the highest ranked concepts genes positively or negativelycorrelated with BRM, an enzymatic subunit of the SWI/SNF chromatinremodeling complex (Roberts et al., Nat Rev Cancer 4, 133-142 (2004))were observed (FIG. 42 a, left). This gene set was generated through ananalysis of the SWI/SNF complex in human prostate cancer samples (Shen,H. et al. Cancer Res 68, 10154-10162, (2008)), making it an attractivebiological insight due to the tissue-specific functions of this complex.This analysis was mirrored by generating gene signatures positive andnegatively correlated to BRM in the RNA-Seq dataset and the enrichmentfor SChLAP-1-regulated genes was confirmed (FIG. 42 a, right).SChLAP-1-regulated genes were inversely correlated with both BRMdatasets (FIG. 42 a). These results demonstrate that SChLAP-1 andSWI/SNF regulate gene transcription in opposing manners, leading to anantagonism of SWI/SNF activity by SChLAP-1.

The SWI/SNF complex operates as a large, multi-protein system thatutilizes ATPase enzymatic activity to physically move nucleosomes and,in doing so, regulates gene transcription (Roberts, C. W. & Orkin, S. H.Nat Rev Cancer 4, 133-142, (2004)). Several SWI/SNF complex members arethe target of recurrent, inactivating mutations in cancer, includingARID1A (Wiegand, K. C. et al. N Engl J Med 363, 1532-1543, (2010);Jones, S. et al. Science 330, 228-231 (2010)), PBRM1 (Varela, I. et al.Nature 469, 539-542 (2011)), and SNF5 (Versteege, I. et al. Nature 394,203-206, (1998)), and numerous studies demonstrate that loss of SWI/SNFfunctionality promotes cancer Progression (Robers et al., supra;Reisman, D., Glaros, S. & Thompson, E. A. Oncogene 28, 1653-1668,(2009)). While SWI/SNF mutations are not commonly observed in prostatecancer, several reports indicate that down-regulation of SWI/SNF complexmembers, particularly BRM, characterizes some subsets of prostate cancer(Sun, A. et al. Prostate 67, 203-213, (2007); Shen, H. et al. Cancer Res68, 10154-10162, (2008)), and mice with a prostate-specific BRM deletionexhibit prostatic hyperplasia and castration-resistant cellularproliferation (Shen et al., supra). Thus, antagonism of SWI/SNF activityby SChLAP-1 is consistent with the oncogenic behavior of SChLAP-1 andthe tumor suppressive behavior of the SWI-SNF complex.

To test whether SChLAP-1 antagonizes SWI/SNF-mediated gene expressionregulation, siRNA knockdown of three key components of the SWI-SNFcomplex: BRM (also known as SMARCA2), BRG1 (also known as SMARCA4), andSNF5 (also known as SMARCB1) was performed. Like BRM, BRG1 serves as anenzymatic subunit of SWI/SNF complex activity, and SNF5 is an essentialsubunit thought to bind histone proteins (Dechassa, M. L. et al. MolCell Biol 28, 6010-6021, (2008)). Knockdown of BRM, BRG1, and SNF5 intwo prostate cell lines, 22Rv1 and LNCaP, followed by expressionmicroarray profiling generated highly overlapping sets of up- anddown-regulated genes, demonstrating that these factors have broadcommonalities in their function in prostate cells. Knockdown of BRM,BRG1 and SNF5 also increased the invasiveness and proliferation rate of22Rv1 cells, consistent with the role of SWI/SNF in tumor suppression.Comparison of genes commonly regulated by knockdown of all SWI/SNFproteins (BRM, BRG1, and SNF5) to genes regulated by SChLAP1demonstrated an antagonistic relationship where SChLAP1 knockdownaffected the same genes as SWI/SNF but in the opposing direction (FIG.42 b). These microarray data were used to generate gene signatures forup- and down-regulated genes upon knockdown of each SWI/SNF protein(BRM, BRG1, and SNF5) and SChLAP-1. The significance of the overlap wasquantitated using GSEA. Performing this analysis across two cell lines(22Rv1 and LNCaP) showed that SWI/SNF and SChLAP-1 affect geneexpression in a highly significant and opposing manner in 23 of 24 totalGSEA comparisons (FDR <0.05) (FIG. 42 c). Together, these datademonstrate that SChLAP-1 functions to modulate SWI/SNF complex activityin prostate cancer.

To examine the mechanism of SChLAP-1 regulation of the SWI/SNF complex,it was examined whether SChLAP-1 regulated SWI/SNF complex genesthemselves. Using Western blots, no change in BRM, BRG1, or SNF5 proteinabundance following SChLAP-1 knockdown or overexpression was detected,demonstrating that SChLAP-1 regulates SWI/SNF activitypost-translationally. Motivated by reports of lncRNAs coordinating thefunction of epigenetic complexes through direct RNA-protein binding, RNAimmunoprecipitation assays (RIP) were performed for SNF5, a core subunitessential for both BRG1 and BRM function, in 22Rv1 and LNCaP cells. Itwas found that endogenous SChLAP-1, but not other prostate-specificlncRNAs such as PCA3 and PCAT-1, robustly bound SNF5 protein (FIG. 42d). RIP for androgen receptor (AR) and SNRNP70, which specifically bindsto the U1 snRNP, served as additional negative controls for theseexperiments (FIG. 42 d).

The role of SChLAP-1-SWI/SNF interactions in the functional role ofSChLAP-1 in inducing cell invasion was tested by evaluatingSChLAP-1-SNF5 binding in the RWPE-SChLAP-1 overexpression model,including overexpression of SChLAP-1 deletion construct #5, which failedto induce cell invasion (FIG. 41 c). Overexpression of both SChLAP-1isoform #1 and isoform #2 robustly bound to SNF5, whereas deletionconstruct 5 (which lacks bps 1001-1250 in SChLAP-1 isoform #1) failed tobind SNF5 (FIG. 42 e). As controls, AK093002 and LOC145837, two lncRNAsupregulated in subsets of prostate cancer that are endogenouslyexpressed in RWPE were measured. Control RIP experiments for SNRNP70demonstrated uniformly strong binding of this protein to U1 in all RWPEcell lines evaluated. Thus, SChLAP-1 regulates SWI/SNF complex activityby directly binding to SWI/SNF proteins through an interaction dependenton base pairs 1001-1250 of the RNA.

To explore a potential link between SChLAP-1 and aggressive prostatecancer associations between SChLAP-1 and gene expression phenotypescurated from published microarray profiling data were explored. Giventhat SChLAP-1 is currently not measured by microarray platforms, asignature of genes with expression significantly correlated oranti-correlated to SChLAP-1 expression in localized tumors was designedand used as a surrogate for SChLAP-1 expression level. The SChLAP-1signature was examined using Oncomine concept analysis (Rhodes, D. R. etal. Neoplasia 9, 166-180 (2007)) and network representations of thesignificantly enriched concepts (p-value <1e-6, odds ratio >3.0) weregenerated. The networks revealed an association with concepts related toprostate cancer progression (FIG. 43 a). Genes positively correlatedwith SChLAP-1 were over-expressed in metastatic and high-grade localizedtumors. Conversely, genes negatively correlated with SChLAP-1 wereunder-expressed in metastatic and high-grade localized tumors.

The analysis was expanded to include four known cancer genes: EZH2, aknown metastasis gene (Kleer, C. G. et al. Proc Natl Acad Sci USA 100;11606-11611, (2003); Varambally, S. et al. Nature 419, 624-629, (2002))PCA3, a lncRNA biomarker over-expressed in prostate cancer and used inprostate cancer diagnosis (de Kok, J. B. et al. Cancer Res 62, 2695-2698(2002); Tomlins, S. A. et al. Sci Transl Med 3, 94ra72, (2011)), AMACR,a tissue biomarker of prostate cancer (Rubin et al., JAMA 287, 1662-1670(2002)), and BRM, a SWI/SNF enzymatic subunit under-expressed inadvanced prostate cancer (Shen et al., supra). Control genes were alsoanalyzed: the nucleoporin genes NUP133 and NUP155, as well as B-actin(ACTB). The expression profiles of each of these seven genes was used toderive correlated and anti-correlated gene sets in the same manner asfor SChLAP-1.

The statistical association between each dataset in the clinical conceptcompendium was analyzed with the gene signatures derived fromcorrelation analysis, including signatures from the RNA-Seq cohortdelineating localized cancer vs. benign tissues, high grade localizedprostate cancer (Gleason ≧8 vs. Gleason 6), and metastatic vs. primarytumors. Odds ratios, p-values, and q-values were calculated for eachcomparison (one-sided Fisher's exact test). A heat-map visualization ofstatistically significant comparisons (q-value <0.01) confirmed a strongassociation of SChLAP-1-correlated genes with high-grade and metastaticcancers as well as poor clinical outcomes (FIG. 43 b). In this respect,SChLAP-1 was highly similar to EZH2, the positive control, which iswidely associated with aggressive, lethal prostate cancer, whereas PCA3and AMACR, two biomarkers not associated with disease progression,strongly associated with Cancer vs. Normal concepts but not conceptsassociated with aggressive disease. Kaplan-Meier analysis ofpublicly-available datasets for biochemical recurrence (Glinsky et al.,J Clin Invest 113, 913-923, (2004)) and overall survival (Setlur, S. R.et al. J Natl Cancer Inst 100, 815-825, (2008)) similarly showedsignificant associations (log rank test, p<0.01) between the SChLAP-1signature and more rapid disease recurrence and decreased survivalprobability.

In order to link SChLAP-1 expression with clinical outcomes directly,Affymetrix exon microarrays, which harbor probes mapping to SChLAP-1exons was used to profile its expression in a prospectively-designedstudy of 235 high-risk prostate cancer patients who underwent radicalprostatectomy between 2000-2006 at the Mayo Clinic (Buerki, C. et al.ASCO Annual Meeting, Abstract #4565 (2012). Nakagawa, T. et al. PLoS One3, e2318, (2008)). Unsupervised clustering was used to define patientsinto low and high SChLAP-1 expression groups and the prognostic utilityof SChLAP-1 was evaluated with three clinical endpoints: biochemicalrecurrence (BCR), clinical progression to systemic disease (CP), andprostate cancer-specific mortality (PCSM). At the time of this analysis,patients had a median follow-up of 8.1 years.

Kaplan-Meier analyses show SChLAP-1 as a powerful single-gene predictorof aggressive prostate cancer (FIG. 43 c-e). SChLAP-1 expression washighly significant when distinguishing CP and PCSM (p=0.00005 andp=0.002, respectively); patients with high SChLAP-1 expression had5-year CP- and PCSM-free survival of only 65% and 85%, respectively,compared to 85% and 95% for patients with low SChLAP-1 expression (FIGS.43 d and 43 e). For the BCR endpoint, high SChLAP-1 expression inpatient primary tumor specimens was associated with a rapid mediantime-to-progression (1.9 vs 5.5 years for SChLAP-1 high and lowpatients, respectively) (FIG. 43 c). These data demonstrate thatSChLAP-1 expression retains its prognostic utility for defining asubgroup of patients more likely to experience BCR, CP, and PCSM even inhigh-risk patients, where most individuals experienced diseaserecurrence within ten years post-prostatectomy (FIG. 43 c). Toindependently validate these findings, the prognostic value of SChLAP-1for BCR was assessed using qPCR on a University of Michigan cohort andconfirmed that SChLAP-1 positive patients are at markedly higher riskfor BCR.

Multivariable and univariable regression analyses of the Mayo Clinicdata demonstrated that SChLAP-1 expression is an independent predictorof prostate cancer aggressiveness with highly significant hazard ratiosfor predicting BCR, CP, and PCSM (HR or 3.045, 0.563, and 4.339,respectively, p<0.01) which were comparable to other clinical factorssuch as Gleason score and advanced clinical stage. Finally,receiver-operator curves (ROC) demonstrated the discriminative abilityof SChLAP-1 expression in the Mayo Clinic dataset witharea-under-the-curve (AUC) values of 0.63, 0.65, and 0.74 for the 5-yearprediction of BCR, CP, and PCSM, which were either equivalent to, orslightly higher than, the AUC values for Gleason score (0.59, 0.65, and0.71, respectively).

Thus, these data demonstrate that SChLAP-1 expression eitherout-performs, or is comparable to, standard clinical parameters such asclinical stage, lymph node invasion, pre-operative serum PSA, surgicalmargin status (SMS) and Gleason score for the prediction of CP, PCSM,and BCR. The particularly strong prognostic value of SChLAP-1 expressionfor CP and PCSM is important, as it is known that patients who developBCR do not necessarily progress further to lethal or clinicallysignificant recurrent disease: that is, many patients who experience BCRnevertheless die with prostate cancer but not from it (Simmons et al.,Eur Urol 51, 1175-1184, (2007); Boorjian, S. A. et al. Eur Urol 59,893-899, (2011)). As such, CP and PCSM represent more stringent criteriato define aggressive prostate cancer. Taken together, the findingsindicate that measurement of SChLAP-1 expression in the earlydevelopment of prostate cancer serves as a valuable biomarker tostratify patient outcomes.

To explore this, SChLAP-1 expression was measured in urine sediment RNAfrom 111 biopsy-confirmed prostate cancer patients with Gleason score.These RNA samples were collected at the time of PSA screening asdescribed previously (Tomlins, S. A. et al. Sci Transl Med 3, 94ra72,(2011)). It was found that SChLAP-1 was significantly higher in Gleason7 patients vs. Gleason 6 patients (Welch's Two Sample t-test,p=0.01498). These data support the utility of SChLAP-1 as a prognosticscreening biomarker for aggressive prostate cancer (Prensner et al., SciTransl Med 4, 127rv123, (2012)).

In conclusion, this example describes a lineage-specific lncRNA that ishighly expressed in 15-30% of prostate cancers but not other tissue orcancer types. In the tissue sets, the sensitivity ranges from 20-35% andthe specificity ranges from 94-100%. SChLAP-1 is highly expressed in asubset of cancers and is thus a highly specific marker for thosecancers. SChLAP-1 directly binds a core subunit in the SWI/SNF complex,leading to reversion of SWI/SNF mediated gene expression (FIG. 44 f). Inmodel systems, SChLAP-1 coordinates prostate cancer cell invasion invitro and metastatic spread in vivo, and in patient tissue samplesSChLAP-1 expression characterizes a metastatic-like gene expressionprofile associated with high-grade localized prostate cancers and poorclinical outcomes. It was further demonstrated that patients with highSChLAP-1 expression are at markedly increased risk for developingmetastatic and lethal prostate cancer.

Table 9 shows genes correlated with SChLAP-1.

TABLE 9 locus nearest_ref_id r p qval chr12: 57180908-57181574 HSD17B6−0.546164551 0.001483863 0.063564631 chr10: 100995269-100995619 HPSE2−0.529744166 0 0 chr9: 4585311-4587469 SLC1A1 −0.528631581 0 0 chr12:104234726-104234975 NT5DC3 −0.52574655 0 0 chr1: 85358698-85358896 LPAR3−0.519067947 0 0 chr7: 12692212-12693228 SCIN −0.513485431 0 0 chr1:204328821-204329044 PLEKHA6 −0.512422441 0 0 chr22: 31674282-31676066LIMK2 −0.50924733 0 0 chr16: 85121881-85127826 KIAA0513 −0.506320229 0 0chr11: 126310080-126310239 ST3GAL4 −0.506170919 0 0 chr2:102855651-102856462 IL1RL2 −0.499389029 0 0 chr2: 100759172-100759201AFF3 −0.498848742 0 0 chr3: 87039767-87040269 VGLL3 −0.49556070.001996514 0.07433842 chr10: 106058885-106059616 GSTO2 −0.481459111 0 0chr18: 78005159-78005429 PARD6G −0.480259815 0.001816685 0.07142087chr5: 14692962-14699820 FAM105B −0.478056706 0.001989958 0.07433842chr11: 124955849-124959131 SLC37A2 −0.477004111 0 0 chr11:134134801-134135749 ACAD8 −0.474921728 0 0 chr12: 104159806-104160505STAB2 −0.474825465 0 0 chr13: 24462816-24463558 MIPEP −0.473774680.000330132 0.017740189 chr15: 89738457-89745591 ABHD2 −0.4736878870.001901732 0.07290082 chr16: 22295207-22297954 EEF2K −0.471488569 0 0chr6: 159185526-159185908 SYTL3 −0.470902458 0 0 chr2:204399833-204400133 RAPH1 −0.469048813 0 0 chr21: 35987058-35987441RCAN1 −0.468923289 0 0 chr2: 242089022-242089679 PASK −0.468525633 0 0chr1: 153603987-153604513 S100A1 −0.467663305 0 0 chr9:77502739-77503010 TRPM6 −0.466199058 0 0 chr5: 66458974-66465423 MAST4−0.464838512 0 0 chr12: 112247346-112247782 ALDH2 −0.464258794 0 0chr20: 33460449-33460663 GGT7 −0.464248542 0 0 chr16: 84695183-84701292KLHL36 −0.462458945 0.001623427 0.067166971 chr5: 55218223-55218678IL31RA −0.462369779 0 0 chrX: 63615219-63615333 MTMR8 −0.462171273 0 0chr16: 84538206-84538296 KIAA1609 −0.461782241 0 0 chrX:18671551-18671749 CDKL5 −0.461589982 0 0 chr10: 94050682-94050844 CPEB3−0.461125435 0 0 chr18: 11908199-11908779 MPPE1 −0.460707259 0 0 chr3:189839991-189840226 LEPREL1 −0.459922767 0.002264726 0.074896868 chr1:154321315-154323783 ATP8B2 −0.459778607 0 0 chr4: 100009839-100009952ADH5 −0.459096821 0 0 chr2: 202028557-202029033 CFLAR −0.454603271 0 0chr11: 130272233-130273133 RP11- −0.453760945 0 0 121M22.1 chr4:106924870-106925184 NPNT −0.453089747 0.001896636 0.07290082 chr17:53809031-53809482 TMEM100 −0.452269788 0 0 chr18: 19102618-19102791GREB1L −0.45014015 0 0 chr7: 128461852-128462186 CCDC136 −0.449966828 00 chr4: 113206795-113207059 TIFA −0.44794294 0 0 chr13:111955337-111958084 ARHGEF7 −0.447155527 0 0 chr7: 103086544-103086624SLC26A5 −0.446130747 0.001571059 0.065901041 chr2: 199436579-199437305PLCL1 −0.445732252 0 0 chr7: 99526462-99527243 GJC3 −0.44536614 0 0chr17: 1613360-1613651 TLCD2 −0.444818675 0.001340945 0.059259314 chr11:44640598-44641913 CD82 −0.444058521 0 0 chr11: 134094990-134095348NCAPD3 −0.443736551 0 0 chr1: 152297664-152297679 FLG −0.442245082 0 0chr18: 8406106-8406859 PTPRM −0.442183213 0 0 chr11: 74178676-74178774KCNE3 −0.44185294 0 0 chr17: 7951703-7952452 ALOX15B −0.440459014 0 0chr3: 49213037-49213918 KLHDC8B −0.440313623 0 0 chr2:219696460-219696809 PRKAG3 −0.440081326 0 0 chr14: 23778024-23780968BCL2L2 −0.438071628 0 0 chr8: 11182824-11182938 AF131216.6 −0.4372712920.00048729 0.025803614 chr14: 77843278-77843396 TMED8 −0.4362736660.002421059 0.07683164 chr8: 22926263-22926692 TNFRSF10B −0.433462746 00 chr11: 118550247-118550399 TREH −0.432052092 0 0 chr8:22471420-22474170 RP11-582J16.5 −0.431261913 0 0 chr14:76668033-76669134 C14orf118 −0.431248632 0 0 chr7: 83277743-83278479SEMA3E −0.430438439 0 0 chr8: 109095151-109095913 RSPO2 −0.428973643 0 0chr6: 42931272-42931618 GNMT −0.427598114 0.000130606 0.007299047 chr1:24795475-24799466 NIPAL3 −0.426835742 0 0 chrX: 148713225-148713568TMEM185A −0.426606945 0 0 chr6: 52860046-52860176 GSTA4 −0.4264871260.002511383 0.077005838 chr11: 4903048-4904113 OR51T1 −0.426468430.002258333 0.074896868 chr20: 45362394-45364965 SLC2A10 −0.4263211360.002038631 0.074404864 chr14: 21167513-21168761 RNASE4 −0.4257698740.00199731 0.07433842 chrX: 23783663-23784592 ACOT9 −0.424946982 0 0chr12: 22218054-22218608 CMAS −0.424346307 0.001493347 0.063820363chr13: 114203739-114204542 TMCO3 −0.423927242 0.001408993 0.06151812chr7: 127233551-127233665 GCC1 −0.423122614 0 0 chr1:168211738-168212378 SFT2D2 −0.422864243 0.001012021 0.048756847 chr7:80551580-80551675 SEMA3C −0.421618187 0.000762726 0.03891404 chr5:149011544-149014531 ARHGEF37 −0.421113016 0.00166369 0.068211282 chr6:125583979-125585553 TPD52L1 −0.420885828 0 0 chr22: 39190072-39190148SUN2 −0.420660125 0 0 chr14: 75201584-75203421 FCF1 −0.420391618 0 0chr4: 142133947-142134031 RNF150 −0.420201646 0.002267743 0.074896868chr6: 159420466-159421219 RSPH3 −0.419873459 0 0 chr7:142637438-142637955 C7orf34 −0.419724438 0.001112591 0.052900521 chr1:38019606-38019905 SNIP1 −0.417392665 0 0 chr12: 112590538-112591407TRAFD1 −0.416676004 0.001376789 0.060695692 chr8: 11643471-11644855NEIL2 −0.415555366 0.000979486 0.047441064 chrX: 99986990-99987110 SYTL4−0.4151136 0 0 chr1: 11865403-11866977 MTHFR −0.414935432 0 0 chr17:19578870-19580909 ALDH3A2 −0.414755637 0 0 chr1: 11322501-11322608 MTOR−0.414459145 0 0 chr22: 29449566-29453475 ZNRF3 −0.414121517 0 0 chr6:3157640-3157809 TUBB2A −0.413596935 0 0 chr17: 12893348-12894960ARHGAP44 −0.413315388 0 0 chr1: 110888929-110889299 RBM15 −0.413119683 00 chr7: 227553-229557 AC145676.2 −0.412677313 0 0 chr21:39288186-39288749 KCNJ6 −0.412229747 0.00154936 0.065292417 chr13:21635484-21635718 LATS2 −0.412031798 0 0 chr3: 68981390-68981761 FAM19A4−0.411387043 0.002212811 0.074896868 chr17: 56032585-56032684 CUEDC1−0.411227218 0.000689134 0.035558916 chr11: 94861540-94865809 ENDOD1−0.411164472 0 0 chr9: 5339535-5339873 RLN1 −0.410338259 0.0016057490.066739616 chr8: 22291403-22291642 SLC39A14 −0.409172508 0.0022731860.074896868 chrX: 2799092-2800859 GYG2 −0.409121519 0 0 chr5:10649377-10650308 ANKRD33B −0.408925428 0 0 chr3: 33138210-33138293TMPPE −0.408755569 0.002067948 0.074404864 chr17: 74639589-74639894ST6GALNAC1 −0.408601974 0 0 chr4: 108871400-108874613 CYP2U1−0.408590838 0 0 chr13: 24476755-24476794 C1QTNF9B −0.4085811 0 0 chr2:222438569-222438922 EPHA4 −0.408496252 0.002565861 0.077672883 chr7:99573567-99573780 AZGP1 −0.408221377 0.001762692 0.070831349 chr11:134188770-134189458 GLB1L3 −0.407453053 0 0 chr15: 90286522-90286868WDR93 −0.407011464 0 0 chr3: 132086547-132087142 ACPP −0.40512191 0 0chr1: 154437609-154441926 IL6R −0.404694713 0 0 chr16: 13328886-13329566SHISA9 −0.404456273 0.00120856 0.054952728 chr3: 184999697-184999778EHHADH −0.404337224 0 0 chr7: 30168881-30170096 PLEKHA8 −0.4040696810.001124581 0.053024689 chr2: 231742722-231743963 ITM2C −0.4040006090.001502313 0.064052833 chr15: 43212635-43213007 TTBK2 −0.403995065 0 0chr5: 78531633-78531861 DMGDH −0.403410254 0.001386979 0.060862399 chr8:105478884-105479281 DPYS −0.403219685 0.006490479 0.118025771 chr20:49307662-49308065 FAM65C −0.40278536 0.001873108 0.072385669 chr16:46796951-46797158 MYLK3 −0.402096842 0.002040434 0.074404864 chr12:27167010-27167367 TM7SF3 −0.401727922 0.003064993 0.083839548 chr4:89205557-89205921 PPM1K −0.400464856 0.001268359 0.057164267 chr6:160199690-160200144 ACAT2 −0.400341345 0.002969949 0.083014679 chr2:179914566-179914813 CCDC141 −0.400161772 0 0 chr18: 48604625-48611415SMAD4 −0.4000199 0.002020762 0.074404864 chr6: 134373515-134373774SLC2A12 −0.399516711 0 0 chr2: 239198539-239198743 PER2 −0.3986484380.001529527 0.064908426 chr3: 195808701-195809060 TFRC −0.3984163670.001122515 0.053024689 chr10: 128994260-128994422 FAM196A −0.3976752550 0 chr19: 18474200-18480763 PGPEP1 −0.397511696 0.001654324 0.067980724chr12: 89913184-89918583 GALNT4 −0.3971679 0.000720157 0.036845671 chr8:27168317-27168836 TRIM35 −0.39698147 0 0 chr12: 112459953-112461255ERP29 −0.396890381 0 0 chr6: 160534453-160534539 IGF2R −0.396621725 0 0chr2: 70052587-70053596 ANXA4 −0.396576146 0 0 chr14: 25518412-25519503STXBP6 −0.396022636 0.00593713 0.114006188 chr15: 90358003-90358094ANPEP −0.39538808 0.001716149 0.069576817 chr2: 219157188-219157309TMBIM1 −0.394985318 0.00305971 0.083821279 chr2: 103459870-103460352TMEM182 −0.393872182 0 0 chr1: 24861582-24863506 RCAN3 −0.392511497 0 0chrX: 19140559-19140755 GPR64 −0.39247745 0 0 chr2: 130886644-130886795POTEF −0.392414695 0.000955249 0.046515259 chr2: 231911596-231914434C2orf72 −0.391887127 0 0 chr8: 142201372-142205907 DENND3 −0.3917940010.001844172 0.072262867 chr12: 47226109-47226191 SLC38A4 −0.3917820930.002190198 0.074896868 chr4: 8442374-8442450 ACOX3 −0.3913467180.005560396 0.110932307 chr17: 65052160-65052913 CACNG1 −0.390171910.001934814 0.073518881 chr22: 34318608-34318829 LARGE −0.3901498960.002219852 0.074896868 chr10: 30404295-30404423 KIAA1462 −0.390135064 00 chrX: 12738647-12742642 FRMPD4 −0.390006756 0.002157606 0.074896868chr4: 75971372-75975325 PARM1 −0.38979558 0.005925405 0.114006188 chr21:47575383-47575481 FTCD −0.389547561 0 0 chr4: 6619106-6625089 MAN2B2−0.38950881 0.001332285 0.059043466 chr16: 4986984-4987136 PPL−0.389314121 0 0 chr5: 140389211-140391929 PCDHA4 −0.389058019 0 0 chr1:150980723-150980854 FAM63A −0.388539406 0.002205328 0.074896868 chr1:94312625-94312706 BCAR3 −0.388149966 0 0 chr3: 48340444-48340743 ZNF589−0.388018199 0.002300474 0.074896868 chr11: 62323634-62323719 AHNAK−0.387645912 0.002464434 0.07690982 chr12: 13366614-13369708 EMP1−0.387372671 0.001560707 0.065618351 chr16: 56458984-56459448 AMFR−0.387021554 0.003775885 0.092303358 chr17: 17875575-17875784 TOM1L2−0.386445952 0.001581429 0.066031038 chr10: 115489069-115490662 CASP7−0.386338815 0.000117675 0.006596685 chr13: 36871773-36871977 C13orf38−0.386125524 0 0 chr10: 73610938-73611126 PSAP −0.386051278 0 0 chr12:63543646-63544722 AVPR1A −0.385980337 0 0 chrX: 70321926-70323385 FOXO4−0.385961192 0 0 chr6: 149394968-149398126 UST −0.385088054 0.0002642320.014369004 chr12: 6346928-6347427 CD9 −0.385058406 0.0020813560.074416668 chr20: 52686971-52687304 BCAS1 −0.384835934 0.0018589840.072287892 chr6: 36891122-36892331 C6orf89 −0.384372572 0.0007051430.036281919 chr18: 55253785-55254004 FECH −0.384344223 0.0022109420.074896868 chr12: 108154733-108155049 PRDM4 −0.384286586 0 0 chr4:87769891-87770416 SLC10A6 −0.383888948 0 0 chr4: 166418663-166419472 CPE−0.38344051 0 0 chr10: 115423569-115423805 NRAP −0.383262593 0.0011991970.054952728 chr18: 59560027-59560992 RNF152 −0.382492767 0.0026215410.078272928 chr21: 34185901-34186053 C21orf62 −0.382395766 0 0 chr1:114515645-114520426 HIPK1 −0.382102457 0.003983912 0.094835898 chr1:235813848-235814054 GNG4 −0.382028045 0.006734515 0.120383578 chr20:36151068-36152092 NNAT −0.381520055 0 0 chr4: 141677069-141677274 TBC1D9−0.381389837 0.007537688 0.126765765 chr15: 90293739-90294541 MESP1−0.381319191 0 0 chr17: 65026581-65029518 CACNG4 −0.3802582120.003303945 0.085620014 chr21: 43735402-43735761 TFF3 −0.37982593 0 0chrX: 71363102-71363424 NHSL2 −0.379789027 0.003306045 0.085620014 chr9:117568082-117568406 TNFSF15 −0.379635338 0.001517712 0.064557866 chr4:111563074-111563279 PITX2 −0.379432657 0.003164641 0.084777841 chr7:7575380-7575484 COL28A1 −0.379174401 0.003048335 0.083821279 chr1:19983358-19984945 NBL1 −0.379105575 0.005009103 0.104695438 chr17:7990613-7991022 ALOX12B −0.37885261 0.004112088 0.09575366 chr4:114899592-114900883 ARSJ −0.378760672 0.008790649 0.13508 chr17:19237268-19240028 EPN2 −0.378663398 0 0 chr1: 162749901-162750237 DDR2−0.378539319 0.004597198 0.100359255 chr10: 117704168-117708503 ATRNL1−0.378216284 0 0 chr15: 39887562-39891119 THBS1 −0.378209064 0 0 chr7:51384289-51384515 COBL −0.378105277 0 0 chr7: 6590638-6591067 GRID2IP−0.378036482 0 0 chr13: 36047925-36050832 MAB21L1 −0.3776656810.002616639 0.078272928 chr5: 171433461-171433877 FBXW11 −0.3772400490.001478969 0.063564631 chr16: 20911525-20911706 DCUN1D3 −0.3771767490.001548826 0.065292417 chr2: 61148897-61150645 REL −0.377068408 0 0chr2: 175351600-175351822 GPR155 −0.376758939 0.001703413 0.069486359chr4: 110222878-110223813 COL25A1 −0.376530527 0 0 chr16:16317255-16317351 ABCC6 −0.376524916 0.002250961 0.074896868 chr14:55611833-55612147 LGALS3 −0.376477741 0.001813224 0.07142087 chr11:6631692-6632102 ILK −0.376273373 0 0 chr20: 8000084-8000476 TMX4−0.37620338 0.002797436 0.080691396 chr2: 23929350-23931481 KLHL29−0.375178691 0.003023736 0.0837197 chr11: 30608288-30608419 MPPED2−0.375114316 0.002532313 0.077155474 chr8: 30585046-30585443 GSR−0.375065559 0.000240196 0.013260404 chr9: 91606384-91611055 C9orf47−0.375058726 0.001854016 0.072262867 chr18: 71958981-71959251 CYB5A−0.374903816 0.002292426 0.074896868 chr10: 43623559-43625799 RET−0.374655986 0.00408246 0.095677062 chr6: 143266235-143266338 HIVEP2−0.374655117 0.004838503 0.102307014 chr11: 74022456-74022702 P4HA3−0.37407796 0.003297931 0.085620014 chr1: 184006228-184006863 GLT25D2−0.373798797 0 0 chr14: 21161705-21162338 ANG −0.373610746 0.0009473530.046379462 chr15: 55581913-55582001 RAB27A −0.372372329 0.0043493010.09789861 chr21: 48084206-48085036 PRMT2 −0.372320011 0.0026114290.078272928 chr12: 130387805-130388211 TMEM132D −0.372252514 0.0024365480.07683164 chr16: 66516774-66519747 AC132186.2 −0.372011859 0 0 chr3:119483898-119485949 C3orf15 −0.371762952 0.002076929 0.074404864 chr11:71707240-71708643 RNF121 −0.371621829 0 0 chr16: 71883526-71891231ATXN1L −0.371120686 0 0 chr19: 38886119-38886868 SPRED3 −0.3707715440.002710805 0.07954175 chr15: 78461263-78464291 IDH3A −0.3707623690.005599722 0.111134243 chr17: 42255572-42256451 ASB16 −0.3705546360.002239895 0.074896868 chr19: 57351949-57352097 ZIM2 −0.3704743270.009388443 0.140270167 chr15: 32695347-32695396 RP13- −0.3703250920.000183582 0.010196928 395E19.1 chr1: 214725657-214725792 PTPN14−0.369408066 0.005749033 0.112400084 chr15: 84962535-84966399 CSPG4P5−0.369128441 0.002286269 0.074896868 chr18: 19284464-19284766 ABHD3−0.369063411 0.002353978 0.075673086 chr3: 113005521-113006303 BOC−0.36895421 0.001134915 0.053127463 chr22: 30685281-30685616 GATSL3−0.368746426 0.001870578 0.072385669 chr15: 42783294-42783336 ZFP106−0.368565346 0.003731514 0.091793135 chr19: 48700486-48700877 C19orf68−0.36851038 0 0 chrX: 120181461-120183794 GLUD2 −0.368504069 0.0032791870.085620014 chrX: 47064319-47065264 INE1 −0.368175848 0.0019880410.07433842 chr5: 125930698-125931110 ALDH7A1 −0.367952163 0.0024837970.076926292 chr12: 10374385-10375727 GABARAPL1 −0.367831123 0.0052975040.108851661 chr1: 209907648-209908295 HSD11B1 −0.367714675 0.0030529390.083821279 chr22: 40366908-40369725 GRAP2 −0.367292326 0.0032088920.085084821 chr2: 171572768-171574588 SP5 −0.367283441 0.0026304790.078272928 chr10: 102745374-102745628 SEMA4G −0.366880776 0 0 chr11:33757927-33757991 CD59 −0.366726455 0.003215396 0.085133002 chr16:69152257-69152622 HAS3 −0.366420617 0.00095903 0.046574504 chr9:119158787-119164601 PAPPA −0.365815146 0.00627853 0.116920758 chr2:227659704-227664475 IRS1 −0.365509755 0.002014141 0.074404864 chr19:46148530-46148726 EML2 −0.364924449 0 0 chr21: 38639538-38640262 DSCR3−0.364678478 0.004475788 0.098672627 chr7: 79082335-79082890 MAGI2−0.364612272 0.005047787 0.105261723 chr12: 102079359-102079796 MYBPC1−0.364376297 0.007651984 0.127947875 chr12: 57350933-57351418 RDH16−0.364373561 0.004448539 0.098538814 chr15: 42500278-42500514 VPS39−0.364232582 0.002353503 0.075673086 chr14: 81864638-81864927 STON2−0.364230778 0.004382182 0.098116492 chr7: 91771776-91772266 CYP51A1−0.364210127 0 0 chr3: 159614511-159615149 SCHIP1 −0.3641867920.002167089 0.074896868 chr2: 238820169-238820756 RAMP1 −0.3636262840.00164314 0.067674286 chr22: 36054661-36057404 APOL6 −0.3635096090.00456657 0.099888173 chr12: 78604177-78606790 NAV3 −0.3631156260.003889133 0.094210495 chr15: 71407467-71407839 CT62 −0.3626199070.000302258 0.016339042 chr1: 182359631-182361341 GLUL −0.3622222520.00311835 0.084283617 chr6: 144385587-144385735 PLAGL1 −0.362216990.006059476 0.11560742 chr18: 57364443-57364574 CCBE1 −0.3619891820.001160655 0.0540538 chr9: 108536145-108538893 TMEM38B −0.361837980.003196865 0.085052362 chr7: 121784214-121784334 AASS −0.3616353560.001030161 0.049499517 chr2: 230135729-230136001 PID1 −0.3613647340.007876988 0.129133025 chr4: 37687821-37687998 RELL1 −0.3613281550.004421037 0.098285551 chr16: 69166386-69166487 CHTF8 −0.3606559970.00397391 0.094764506 chr1: 184943433-184943682 FAM129A −0.3605294440.003171679 0.084841251 chr12: 56112874-56113871 BLOC1S1 −0.3603324240.002460351 0.07690982 chr5: 40691880-40693837 PTGER4 −0.360302037 0 0chr20: 48098450-48099184 KCNB1 −0.360156699 0.005928121 0.114006188chr14: 91282518-91282761 TTC7B −0.36000688 0.002911014 0.08228265 chr2:169721343-169722024 NOSTRIN −0.359423859 0.002183004 0.074896868 chr19:47290656-47291851 SLC1A5 −0.358711445 0 0 chr2: 111875192-111875799ACOXL −0.358659464 0.00272735 0.079641256 chr7: 84815993-84816171 SEMA3D−0.358554714 0.008937979 0.1364206 chr16: 75528837-75529282 CHST6−0.358161822 0 0 chr1: 46216268-46216322 IPP −0.358130707 0.0020618590.074404864 chr15: 30706317-30706463 AC019322.1 −0.35739784 0.0032956660.085620014 chr9: 4662297-4665256 PPAPDC2 −0.357393072 0.0085395270.133479717 chr14: 23904828-23904927 MYH7 −0.357022956 0.0002518270.013818534 chr5: 42887392-42887494 SEPP1 −0.356433723 0.0046182620.10049394 chr10: 53455246-53459355 CSTF2T −0.356077989 0.0053947850.109381082 chr1: 82456074-82458107 LPHN2 −0.35586493 0.008725940.134884462 chr20: 5170747-5178533 CDS2 −0.355827803 0.0019592110.074231845 chr14: 20881563-20881580 TEP1 −0.355558706 0 0 chr17:62207335-62207502 ERN1 −0.355198611 0.003341644 0.085969228 chr22:24890657-24891042 C22orf45 −0.355112593 0.006216471 0.116920758 chr7:148112508-148118090 CNTNAP2 −0.355018684 0.003900583 0.094210495 chrX:100786630-100788446 ARMCX4 −0.354773706 0.001780023 0.071212674 chr9:100845127-100845357 NANS −0.354741743 0.00322612 0.085267223 chr11:85338261-85338966 DLG2 −0.35458979 0.007531741 0.126765765 chr10:36810648-36813162 NAMPTL −0.354542215 0.003272356 0.085620014 chr3:51418480-51421629 DOCK3 −0.354499487 0.009000821 0.136900167 chr11:119170204-119177651 CBL −0.354474684 0 0 chr7: 92465791-92465908 CDK6−0.354190236 0.007309538 0.124777387 chrX: 110463585-110464173 PAK3−0.353473303 0.00372339 0.091761103 chr1: 213445866-213448116 RPS6KC1−0.353132762 0.008090944 0.130860029 chr1: 203144678-203144941 MYBPH−0.353031224 0 0 chr12: 110205816-110208312 C12orf34 −0.3529271220.003855714 0.093875787 chr1: 54483764-54483856 LDLRAD1 −0.3523683950.002200147 0.074896868 chr8: 92052871-92053292 TMEM55A −0.3521255830.00424435 0.096531516 chr15: 90890818-90892669 GABARAPL3 −0.3520966210.004075199 0.09564239 chr5: 126801297-126801429 MEGF10 −0.3519790710.005769117 0.112671479 chr7: 66273872-66276446 KCTD7 −0.3517874580.008500777 0.133361292 chr12: 101521638-101522419 ANO4 −0.3516612050.00536422 0.109252525 chr6: 3231790-3231964 TUBB2B −0.3508360480.00415823 0.095871025 chr14: 76446884-76448092 TGFB3 −0.3508206310.007016608 0.121921113 chr2: 178972980-178973081 PDE11A −0.3503376320.005792206 0.113000905 chr11: 114121047-114121398 ZBTB16 −0.3499825480.007051836 0.122091644 chr3: 97471032-97471304 EPHA6 −0.3497487720.004669226 0.100960902 chr18: 72775105-72777628 ZNF407 −0.3495955330.011713078 0.154835981 chr17: 40540296-40540449 STAT3 −0.349348115 0 0chr16: 90095315-90096309 C16orf3 −0.349062505 0.002890689 0.082124567chr17: 76899215-76899297 AC100788.1 −0.349055229 0.004954969 0.104163323chr2: 11780416-11782914 GREB1 −0.348390425 0.004885601 0.103182756 chr3:169487108-169487683 AC078802.1 −0.348375436 0.006616271 0.118981508chr15: 64126025-64126147 HERC1 −0.348284478 0.004634897 0.10069813 chr7:102301592-102301847 RP11-577H5.4 −0.348203645 0 0 chr2:169764077-169766505 G6PC2 −0.347521745 0.000531991 0.027845969 chr10:127697622-127698161 FANK1 −0.346440794 0.003260067 0.085620014 chr1:68153343-68154021 GADD45A −0.346346476 0.008456687 0.133216661 chr14:93651154-93651260 MOAP1 −0.34606439 0 0 chr9: 102625901-102629173 NR4A3−0.346030498 0.004972561 0.10429172 chr20: 42939615-42939809 FITM2−0.345997257 0.004756964 0.101816018 chr2: 239139841-239140318AC016757.3 −0.3458947 0.004187488 0.096032 chr4: 175443509-175444305HPGD −0.345861904 0.002242854 0.074896868 chr1: 24740163-24743424C1orf201 −0.345686354 0.005986125 0.114759271 chr1: 113499460-113499635SLC16A1 −0.345488279 0.009716079 0.142148692 chr10: 14816251-14816896FAM107B −0.345316938 0.001800119 0.071315614 chr12: 85429981-85430055TSPAN19 −0.345103145 0.006226591 0.116920758 chr16: 88634958-88636548C16orf85 −0.345097604 0.001129539 0.053024689 chr4: 100212053-100212185ADH1A −0.344998373 0.004254851 0.096531516 chr8: 1728415-1734738 CLN8−0.344633185 0.010423843 0.14552518 chr11: 67124213-67124443 POLD4−0.344486773 0.002625331 0.078272928 chr14: 102964439-102968809 TECPR2−0.344287946 0.00249821 0.076926292 chr19: 45826078-45826233 CKM−0.344265976 0.002432096 0.07683164 chr6: 20212366-20212670 MBOAT1−0.343916793 0.005876217 0.113663186 chr9: 130869307-130871524 SLC25A25−0.343624793 0 0 chr9: 86258343-86259045 C9orf103 −0.3434448270.002600596 0.078272928 chr11: 626020-626078 CDHR5 −0.3431877870.008441373 0.133216661 chr16: 88729418-88729518 MVD −0.3431376680.004619966 0.10049394 chr12: 52470569-52471278 C12orf44 −0.3430561360.000630237 0.032893644 chr3: 143767509-143767561 C3orf58 −0.3423287680.006331044 0.117217889 chr16: 76592386-76593135 CNTNAP4 −0.3421029190.000790908 0.040014672 chr6: 139113885-139114456 CCDC28A −0.3419860120.006517637 0.118025771 chr17: 33513317-33516364 UNC45B −0.3419372410.003818629 0.093222797 chr10: 135336774-135337062 RP11- −0.3419035640.006813291 0.120821721 108K14.4 chr2: 242162600-242164792 ANO7−0.341869694 0.007132564 0.123028262 chr4: 7940727-7942023 AC097381.1−0.341732589 0.008108444 0.131026389 chr19: 35614344-35615227 FXYD3−0.341197928 0.006740632 0.120383578 chr10: 81373492-81375197 SFTPA1−0.341146486 0.001850992 0.072262867 chr11: 125301061-125303285 PKNOX2−0.341144084 0.003301426 0.085620014 chr8: 27401960-27403081 EPHX2−0.34107733 0.004448705 0.098538814 chr16: 81411019-81413940 GAN−0.341026233 0.002661769 0.078610908 chr2: 179695391-179695529 TTN−0.340871763 0.003439286 0.087240779 chr3: 49761030-49761384 GMPPB−0.340818196 0.006392303 0.117755656 chr11: 125366403-125369424AP000708.1 −0.340419481 0.007994613 0.12969294 chr8: 27337285-27337400CHRNA2 −0.340317829 0.01017339 0.143603022 chr6: 170713850-170716153FAM120B −0.340145296 0.006394353 0.117755656 chr19: 52034835-52035110SIGLEC6 −0.339935646 0.00249674 0.076926292 chr2: 169952053-169952677DHRS9 −0.339663644 0 0 chr8: 121825324-121825513 SNTB1 −0.3392205590.013026815 0.159180228 chr10: 61122866-61122939 FAM13C −0.3391167880.012107259 0.155429477 chr7: 98030113-98030380 AC093799.1 −0.3390898570.002803296 0.080691396 chr5: 131630870-131631008 P4HA2 −0.3388628660.004018835 0.095037797 chrX: 112083679-112084043 AMOT −0.3387432630.009557513 0.141580566 chr3: 113346492-113348425 SIDT1 −0.3381823280.016461828 0.175467239 chr1: 111893880-111895635 C1orf88 −0.3378563320.00901587 0.136919096 chr13: 111521577-111522162 C13orf29 −0.337754450.002559298 0.077611339 chr1: 201860927-201861434 SHISA4 −0.3377164350.002153764 0.074896868 chr11: 134019040-134021896 JAM3 −0.3377082930.002445067 0.07690982 chr7: 49951629-49952138 VWC2 −0.337645170.005162659 0.106835773 chr12: 46663762-46663800 SLC38A1 −0.337636810.009933718 0.143081782 chr17: 71258247-71258491 CPSF4L −0.3375248210.006504807 0.118025771 chr1: 156108870-156109880 LMNA −0.337501786 0 0chr19: 30205813-30206364 C19orf12 −0.337294662 0.009407927 0.140292428chr7: 134264258-134264592 AKR1B15 −0.337020674 0.005585004 0.111106714chr7: 4897363-4901625 PAPOLB −0.336643583 0.009833222 0.142636167 chr2:11317862-11319000 PQLC3 −0.33652056 0.013477235 0.162218034 chr14:39900767-39901704 FBXO33 −0.336362403 0.004102791 0.09575366 chr9:131703723-131704320 PHYHD1 −0.336138287 0 0 chr1: 221915322-221915518DUSP10 −0.33590192 0.012733827 0.158213348 chr3: 41301355-41301587CTNNB1 −0.335633668 0.006267131 0.116920758 chr4: 31144094-31144728PCDH7 −0.335237096 0.005140064 0.106574171 chr1: 203765436-203769686ZBED6 −0.335082465 0.003469323 0.087293121 chr19: 3543826-3544028C19orf71 −0.334820013 0.004225675 0.096464363 chr22: 43117170-43117304A4GALT −0.33461522 0 0 chr15: 99791359-99791422 TTC23 −0.3346073610.009988191 0.143216183 chr16: 5064859-5069156 SEC14L5 −0.334522135 0 0chr5: 32786339-32787256 NPR3 −0.334311711 0.005412112 0.10946569 chr2:160918805-160919121 PLA2R1 −0.334063845 0.005422954 0.109562966 chr4:108955394-108956331 HADH −0.334047223 0.005989748 0.114759271 chr3:14814297-14814541 C3orf20 −0.333760773 0.004507549 0.099237103 chr20:55100838-55100981 GCNT7 −0.333749414 0.008434475 0.133216661 chr10:43762292-43762367 RASGEF1A −0.333319387 0.001430906 0.06194304 chr5:80561957-80562216 CKMT2 −0.333284313 0.005483096 0.109968839 chr6:41031839-41032465 APOBEC2 −0.333213576 0.004677515 0.10098106 chr9:5304369-5304969 RLN2 −0.333058195 0.005460123 0.109968839 chr1:181057637-181059977 IER5 −0.332972834 0 0 chr12: 50236168-50236912BCDIN3D −0.332717732 0.007849382 0.129133025 chr14: 95942014-95942173C14orf49 −0.332614322 0.008380922 0.133216661 chr13: 24247510-24250232TNFRSF19 −0.332405917 0.0118646 0.155153269 chr3: 38178355-38178733ACAA1 −0.332380373 0.005375471 0.109333343 chr10: 62761156-62761198RHOBTB1 −0.332293978 0.008639609 0.134263631 chr14: 24114350-24114848DHRS2 −0.332200435 0.009216563 0.138576518 chr19: 53077329-53077383ZNF808 −0.332184126 0.004142985 0.095871025 chrX: 67944146-67945684STARD8 −0.332156945 0.005297851 0.108851661 chr22: 17612504-17612994AC006946.15 −0.332029863 0.002076087 0.074404864 chr15:100273489-100273766 LYSMD4 −0.33196355 0.004818502 0.102159863 chr19:57802066-57805436 ZNF460 −0.331805696 0.0062541 0.116920758 chr1:110052041-110052360 AMIGO1 −0.331748977 0.007140297 0.12304479 chr19:40931773-40931932 SERTAD1 −0.331603747 0.004097877 0.09575366 chr1:235667440-235667781 B3GALNT2 −0.331355681 0.006921811 0.121704609 chr5:180631588-180632293 TRIM7 −0.331070531 0.00478817 0.102074564 chr7:134849169-134850650 TMEM140 −0.330961226 0.006462905 0.118025771 chr1:203054618-203055164 MYOG −0.330806046 0 0 chr22: 24836550-24838328ADORA2A −0.330604462 0.009903173 0.143081782 chr14: 59950207-59951148C14orf149 −0.330342745 0.011107988 0.150003266 chr17: 62833173-62833243AC103810.1 −0.330067269 0.004228881 0.096464363 chr3:159614511-159615155 IQCJ-SCHIP1 −0.329859948 0.000512092 0.026881861chr22: 43411026-43411151 PACSIN2 −0.329641143 0.00529232 0.108851661chr3: 143566989-143567373 SLC9A9 −0.329499509 0.00957653 0.141580566chr6: 147705849-147708707 STXBP5 −0.329411447 0.005615759 0.111134243chr10: 43991463-43991517 ZNF487P −0.329209459 0.004820294 0.102159863chr6: 123384818-123385612 CLVS2 −0.328460279 0.004405369 0.098228128chr2: 168114366-168116263 XIRP2 −0.328456174 0.001905952 0.07290082chr11: 70281131-70282690 CTTN −0.328378509 0.005485425 0.109968839 chr1:39876150-39882154 KIAA0754 −0.328304607 0.009074575 0.137166781 chr21:47648347-47648738 LSS −0.32811765 0.006302121 0.116920758 chr8:75233143-75233563 JPH1 −0.327851537 0.005395884 0.109381082 chr17:46135656-46138906 NFE2L1 −0.327788072 0.002131117 0.074896868 chr3:196065134-196065374 TM4SF19 −0.327643438 0.004075715 0.09564239 chr17:11461070-11462196 SHISA6 −0.327641088 0.003501168 0.08783387 chr7:97841565-97842271 BHLHA15 −0.327621915 0.007927854 0.129538147 chr11:4730834-4731698 AC103710.1 −0.327522873 0.003710943 0.091703214 chr10:75457290-75457639 AGAP5 −0.327417008 0.00230532 0.074904336 chr2:204599506-204602557 CD28 −0.327340798 0.003182194 0.084997327 chr1:200143090-200146552 NR5A2 −0.327072728 0.000350694 0.01878955 chr5:140890513-140892542 PCDHGC3 −0.326986718 0 0 chr17: 4926762-4931696KIF1C −0.326823547 0.00581312 0.11307866 chr2: 182794287-182795465 SSFA2−0.326707409 0.006909184 0.121600292 chr6: 159240348-159240444 EZR−0.326642824 0.006782665 0.120633891 chr8: 12613432-12613582 LONRF1−0.326542762 0.001910521 0.07290082 chr11: 111789401-111789574AP000907.1 −0.326455419 0.006026463 0.115098472 chr8: 74235147-74237516RDH10 −0.326283654 0 0 chr9: 36276890-36277053 GNE −0.3262530350.007726033 0.128531382 chr11: 66725792-66725847 PC −0.325978540.002534333 0.077155474 chr14: 23834216-23834961 EFS −0.3259105540.005541994 0.110736224 chr17: 46198596-46200105 SNX11 −0.3254040340.00435117 0.09789861 chr22: 50450973-50451088 IL17REL −0.3250244920.006764548 0.120633891 chr21: 34265885-34266043 C21orf49 −0.3249016110.003697375 0.091617209 chr5: 135223720-135224326 SLC25A48 −0.3244914410.004700972 0.101165586 chr11: 31451817-31453396 DNAJC24 −0.3240353190.007961992 0.12969294 chr16: 69117387-69119083 TMCO7 −0.3239307140.001996814 0.07433842 chr11: 5256444-5256600 HBD −0.3234157610.006496377 0.118025771 chr11: 60543077-60544205 MS4A15 −0.3233069540.005827077 0.113194863 chr19: 34991033-34992085 WTIP −0.3232880910.003628394 0.09052543 chr21: 33765077-33765335 URB1 −0.3226052340.007661761 0.127947875 chr11: 107590341-107590419 SLN −0.322593010.003198302 0.085052362 chr1: 16332413-16335302 C1orf64 −0.3225711140.003329308 0.085908111 chr14: 52793938-52795324 PTGER2 −0.322544010.00584014 0.113206474 chr7: 100734918-100735017 TRIM56 −0.322093460.006276926 0.116920758 chr4: 6302383-6304992 WFS1 −0.3218695960.006860626 0.121215509 chr14: 65007185-65009955 HSPA2 −0.3216076550.004372355 0.098043319 chr10: 92680757-92681033 ANKRD1 −0.321498680.004154414 0.095871025 chr2: 169887734-169887832 ABCB11 −0.321337647 00 chr2: 100937876-100939195 LONRF2 −0.321330932 0.006819887 0.120821721chr3: 9934492-9936033 JAGN1 −0.32116212 0.00609355 0.116013774 chr7:1097127-1098897 GPR146 −0.320796122 0.005512112 0.110317975 chr22:24236884-24237414 MIF −0.320238374 0.003304999 0.085620014 chr10:17171642-17171830 CUBN −0.3201406 0.006228317 0.116920758 chr11:70052238-70053496 FADD −0.320086207 0.005320566 0.109004718 chr10:120355027-120355160 PRLHR −0.319837349 0.001458704 0.062932162 chr1:6674509-6674667 KLHL21 −0.319337027 0.004808398 0.102159863 chr1:167095023-167098402 DUSP27 −0.31926543 0.003356573 0.086049007 chr5:176730009-176730745 RAB24 −0.319255928 0.003368433 0.086049007 chr20:55093142-55093943 C20orf43 −0.319042706 0.006112598 0.116162907 chr5:140389211-140391929 PCDHA13 −0.318776843 0.005901557 0.113959318 chr4:186320723-186321782 ANKRD37 −0.318309287 0.006407439 0.117791816 chrX:138790264-138790386 MCF2 −0.318200097 0.003906063 0.094217569 chr12:124242473-124245549 ATP6V0A2 −0.318185391 0.005692545 0.112019177 chr2:211179634-211179914 MYL1 −0.318151264 0.004475644 0.098672627 chr1:232172439-232177018 DISC1 −0.317969164 0.006350874 0.117465307 chr9:99381500-99382112 CDC14B −0.317910194 0.004163307 0.095871025 chr1:223175726-223179337 DISP1 −0.317844696 0.003050324 0.083821279 chr12:53646601-53648189 MFSD5 −0.317723142 0 0 chr22: 50050271-50051190C22orf34 −0.317628122 0.004257102 0.096531516 chr6: 30523907-30525008GNL1 −0.317139954 0 0 chr3: 11596284-11599139 ATG7 −0.31694580.002281379 0.074896868 chr16: 71264464-71264625 HYDIN −0.3168061170.004731057 0.101554491 chr11: 125136535-125136741 RP11- −0.3166008320.003883559 0.094210495 687M24.6 chr12: 113797134-113797298 SLC24A6−0.315121613 0.004109022 0.09575366 chr11: 66113960-66115163 B3GNT1−0.314657476 0.00480751 0.102159863 chr7: 128498389-128499328 FLNC−0.312046294 0.006196778 0.116920758 chr11: 35441454-35441610 SLC1A2−0.311887865 0.004570119 0.099888173 chr20: 61167650-61167971 C20orf166−0.311455851 0.006090275 0.116013774 chrX: 37312388-37316548 PRRG1−0.311450759 0.002311383 0.074967239 chr6: 3152721-3153812 BPHL−0.311242496 0.003734797 0.091793135 chr7: 31697884-31698334 CCDC129−0.311051556 0.002109037 0.074896868 chr1: 26393826-26394927 TRIM63−0.309913705 0.005735635 0.112400084 chr20: 6034475-6034695 LRRN4−0.309273385 0.001724002 0.069739517 chr5: 80689806-80689998 ACOT12−0.308117282 0.003117847 0.084283617 chr8: 33330581-33330940 FUT10−0.307474854 0.003443905 0.087240779 chr1: 182558301-182558391 RNASEL−0.307317477 0.005481298 0.109968839 chr7: 107443555-107443670 SLC26A3−0.307261592 0.003057062 0.083821279 chr10: 76868766-76868976 DUSP13−0.306383849 0.004406938 0.098228128 chr19: 54984210-54984411 CDC42EP5−0.305854117 0.002282771 0.074896868 chrX: 118699087-118699397 CXorf56−0.304902726 0.002049412 0.074404864 chr11: 34492914-34493609 CAT−0.303602311 0.004918322 0.103512716 chr15: 101454905-101456831 ALDH1A3−0.303374031 0.005729864 0.112400084 chr17: 10325246-10325267 MYH8−0.303265671 0.001915237 0.072927569 chr1: 45792544-45794347 HPDL−0.302015312 0.005632886 0.111327654 chr1: 162838442-162838605 C1orf110−0.300571972 0 0 chr6: 39869588-39872648 DAAM2 −0.299895021 0.003302180.085620014 chr11: 68855342-68858072 TPCN2 −0.299814629 0.0049063770.103387608 chr2: 28634745-28640179 FOSL2 −0.299377859 0.0046618070.100960902 chr22: 20137990-20138399 AC006547.14 −0.2952164070.002654087 0.078584121 chr19: 4867620-4867780 PLIN3 −0.2926011410.005346359 0.109247654 chrX: 152760831-152760978 HAUS7 −0.2890268840.00546317 0.109968839 chr7: 54636701-54638773 VSTM2A −0.2860771720.004209951 0.096303956 chr5: 180000987-180005405 CNOT6 0.2801624960.004272958 0.096770254 chr8: 56685785-56685966 TMEM68 0.2807394170.004369285 0.098043319 chr14: 97031291-97033425 PAPOLA 0.281547470.002912941 0.08228265 chr8: 66545953-66546442 ARMC1 0.2817852490.005362125 0.109252525 chr15: 49170297-49172190 EID1 0.2888539490.005164445 0.106835773 chr1: 226496809-226497570 LIN9 0.2918295680.004543724 0.099671077 chr17: 57970057-57970296 TUBD1 0.2931824010.004441351 0.098538814 chr4: 148593017-148593195 TMEM184C 0.293710605 00 chr15: 38776455-38779911 FAM98B 0.294672563 0.002073568 0.074404864chr20: 47712344-47713489 CSE1L 0.296532783 0.002844634 0.081237547 chr5:56558420-56560505 GPBP1 0.297506006 0 0 chr12: 58350469-58351052XRCC6BP1 0.298404618 0.005616981 0.111134243 chr19: 44284854-44285409KCNN4 0.299794156 0.001595016 0.066445584 chr17: 30325676-30328064 SUZ120.300313931 0.002768918 0.080210303 chr5: 140698056-140700330 TAF70.30034378 0.004413046 0.098228128 chr1: 185069331-185071740 RNF20.300817006 0.002256081 0.074896868 chr17: 58023911-58027925 RPS6KB10.301654892 0.002463315 0.07690982 chr1: 151881835-151882284 THEM40.303048607 0.003891008 0.094210495 chr3: 196555189-196559518 PAK20.304684107 0.00565642 0.111550003 chr3: 56655559-56655846 CCDC660.305496446 0.004722128 0.101500611 chr9: 130457272-130457460 STXBP10.306449217 0.002610067 0.078272928 chr6: 84418064-84419410 SNAP910.306744409 0.00289378 0.082124567 chr18: 267965-268059 THOC10.308452954 0.002246863 0.074896868 chr11: 126174102-126174213RP11-712L6.5 0.308555738 0.001968874 0.074231845 chr1: 92764481-92764544GLMN 0.309420667 0.005838193 0.113206474 chr5: 68709857-68710628 RAD170.309947634 0.002036157 0.074404864 chr12: 51566083-51566926 TFCP20.310337811 0.002022616 0.074404864 chr12: 133532828-133532892 ZNF6050.310370533 0.005741782 0.112400084 chr3: 69129484-69129559 UBA30.311955874 0.004476434 0.098672627 chr2: 44222912-44223144 LRPPRC0.311969209 0.005806947 0.11307866 chr12: 106697789-106698057 CKAP40.31330448 0.005323305 0.109004718 chr19: 11978120-11980306 ZNF4390.31399977 0.000679969 0.03518595 chr17: 30714772-30714780 ZNF2070.314664535 0.004663714 0.100960902 chr3: 178984436-178984790 KCNMB30.315313767 0.000492826 0.026020926 chr3: 3192223-3192563 TRNT10.315943006 0.005904075 0.113959318 chr2: 37193372-37193615 STRN0.316227369 0.004355122 0.09789861 chr19: 34718269-34720420 LSM14A0.316229966 0.005347198 0.109247654 chr5: 86708251-86708836 CCNH0.31651571 0.002288526 0.074896868 chr19: 12662143-12662327 ZNF5640.316577163 0.001969925 0.074231845 chr19: 23941548-23941693 ZNF6810.316870966 0.003718019 0.091753239 chr2: 203103162-203103331 SUMO10.317470493 0.00313409 0.08454882 chr11: 85563599-85565986 AP000974.10.31748757 0.00585565 0.113386114 chr14: 39649706-39652422 PNN0.317832199 0.006385595 0.117755656 chr8: 142012112-142012315 PTK20.318325276 0.003146205 0.084658552 chr20: 57617753-57617964 SLMO20.319001046 0.005278416 0.108821635 chr13: 47371239-47371367 ESD0.319016641 0.003463992 0.087293121 chr21: 40721385-40721573 HMGN10.319212709 0 0 chr7: 79846618-79848718 GNAI1 0.320340043 0.0044119030.098228128 chr19: 57764440-57774106 ZNF805 0.320363681 0.0053851120.109381082 chr16: 3367189-3368574 ZNF75A 0.320482104 0.0021818620.074896868 chr15: 60771201-60771344 NARG2 0.321091259 0.0041759770.095889084 chr17: 8286474-8286568 RPL26 0.321101419 0.0037605750.092052993 chr6: 168720067-168720434 DACT2 0.321179692 0.0024071790.076804143 chr14: 35008760-35008943 EAPP 0.321340899 0.0045346680.099592725 chr2: 99921102-99921205 LYG1 0.321471395 0.00622960.116920758 chr13: 41701704-41706882 KBTBD6 0.321594919 0.0041734260.095889084 chr5: 140602930-140605858 PCDHB14 0.322104178 0.0062331770.116920758 chr12: 75905292-75905416 KRR1 0.322196506 0 0 chr7:29552179-29553944 CHN2 0.322296255 0.002750261 0.080052876 chr19:19843764-19843921 ZNF14 0.322336899 0.004015145 0.095037797 chr11:75851754-75854239 UVRAG 0.322461087 0.005592429 0.111132704 chr3:93747210-93747454 STX19 0.322908263 0.006898306 0.121600292 chr17:65739858-65740318 NOL11 0.323132613 0.00348465 0.087540376 chr16:28331396-28335170 SBK1 0.324007796 0.005584472 0.111106714 chr11:125825711-125826214 RP11- 0.324171654 0.007187233 0.123441982 680F20.6chrY: 21765682-21768160 CYorf15B 0.324250683 0 0 chr15:59949322-59949740 GTF2A2 0.324886639 0.00679345 0.120633891 chr8:141524392-141527236 CHRAC1 0.325103238 0.006576969 0.1185295 chr1:46153654-46153785 GPBP1L1 0.325228449 0.00663606 0.119219352 chr18:33558797-33559241 C18orf21 0.325286794 0.00452516 0.099504209 chr19:35174896-35177302 ZNF302 0.325802707 0.003260401 0.085620014 chr4:170192009-170192256 SH3RF1 0.326613568 0.008264705 0.132373754 chr10:74927623-74927853 ECD 0.326731314 0.005005407 0.104695438 chr5:170738392-170739138 TLX3 0.326740102 0.007724752 0.128531382 chr2:217069910-217071026 XRCC5 0.327063734 0.004964977 0.104253046 chr16:3458320-3459370 ZNF174 0.32719442 0.005999522 0.114825412 chr8:82644987-82645138 ZFAND1 0.327291564 0.004906685 0.103387608 chr2:238166072-238166319 AC112715.2 0.327628695 0.006988291 0.121921113chr22: 41252434-41253026 ST13 0.327785232 0.006664518 0.119612287 chr19:21950228-21950330 ZNF100 0.328529297 7.16E−05 0.00404126 chr1:95007092-95007356 F3 0.328897709 0.003923792 0.0943921 chr12:72070468-72074419 THAP2 0.328949319 0.000936046 0.045949726 chr13:37633616-37633850 FAM48A 0.329201798 0 0 chr2: 136481506-136482840R3HDM1 0.329264663 0.004476477 0.098672627 chr9: 66553673-66555928 RP11-0.329390698 0.004136364 0.095871025 262H14.4 chr13: 41345120-41345309MRPS31 0.329399968 0.001803178 0.071315614 chr17: 4994791-4999668 ZFP30.329822496 0.00706482 0.122091644 chr1: 151141461-151142773 SCNM10.330275788 0.004023788 0.095037797 chr11: 32623824-32627808 EIF3M0.330560474 0.007052809 0.122091644 chr8: 42029046-42029191 AP3M20.330606328 0.005212564 0.107708532 chr11: 64338450-64340347 SLC22A110.330712435 0.003990159 0.094844827 chr3: 32814948-32815367 CNOT100.330830953 0 0 chrX: 15682840-15683154 TMEM27 0.330831688 0.0061141740.116162907 chr19: 36909393-36909558 ZFP82 0.330854448 0.0003086350.016634253 chr14: 23240642-23241007 OXA1L 0.330898021 0.0090774910.137166781 chr7: 64291828-64294054 ZNF138 0.33092203 0.0042473020.096531516 chr14: 30661071-30661104 PRKD1 0.331146193 0.0074247710.125564356 chr9: 100777645-100778225 ANP32B 0.331404852 0.0088780.136076888 chr6: 10419650-10419892 TFAP2A 0.331452981 0.007750690.128531382 chr15: 23334999-23335196 AC091565.1 0.331545817 0.0025595550.077611339 chr17: 58156056-58156292 HEATR6 0.331671707 0.006248910.116920758 chr11: 73964536-73965748 PPME1 0.33178239 0.0114639330.153440983 chr19: 56347701-56348128 NLRP11 0.332151069 0.0039666340.094764506 chr3: 64009480-64009658 PSMD6 0.332227431 0.0047358180.101554491 chr15: 40331293-40331389 SRP14 0.332257211 0.0097451370.142230949 chr15: 29409264-29410518 APBA2 0.332585829 0.008208060.132028532 chr10: 60588520-60591195 BICC1 0.332588003 0.0058148690.11307866 chr16: 47177489-47177908 NETO2 0.33260473 0.0029896260.083076103 chr10: 124713530-124713919 C10orf88 0.332876872 0.0029937040.083076103 chr9: 127951840-127952218 PPP6C 0.332984853 0.0039947310.094844827 chr1: 151735802-151736040 MRPL9 0.333136616 0.0041956750.096098418 chr4: 120325655-120326749 AC110373.1 0.333522527 0.0042328960.096464363 chr1: 152020297-152020383 S100A11 0.333566613 0.0078538170.129133025 chrX: 24094838-24096088 EIF2S3 0.333582575 0.0030719930.083904667 chr2: 207582984-207583120 DYTN 0.333890074 0.0143674990.165520063 chr4: 146048677-146050331 ABCE1 0.333925697 0.0030893870.084000815 chr2: 109492543-109493034 CCDC138 0.333976981 0.0043499290.09789861 chr2: 231989685-231989832 HTR2B 0.334198112 0.0041532720.095871025 chr11: 59436353-59436471 PATL1 0.334333206 0.0079834680.12969294 chr11: 58384668-58388515 ZFP91 0.334555856 0 0 chr12:120315052-120315095 CIT 0.334566849 0.012110335 0.155429477 chr9:97090889-97090926 FAM22F 0.334602902 0.008513342 0.133361292 chr8:103136797-103137135 NCALD 0.334783433 0 0 chr2: 99797169-99797521 MITD10.33494044 0.001482186 0.063564631 chr5: 140579182-140582618 PCDHB110.335046305 0.003710523 0.091703214 chr11: 66610639-66610987 C11orf800.335296837 0.003954429 0.094764506 chr12: 93894951-93897545 MRPL420.335324039 0.002410305 0.076804143 chr20: 21695108-21696620 PAX10.335448884 0.007190531 0.123441982 chr5: 134735438-134735604 H2AFY0.335582907 0.007328985 0.124979581 chr1: 235611984-235612283 TBCE0.335596516 0.003395192 0.086368012 chr19: 51538050-51538486 KLK120.335737191 0.00967498 0.142148692 chr18: 12884071-12884337 PTPN20.336004992 0.002423347 0.07683164 chr9: 19102521-19103117 HAUS60.336050358 0.00392889 0.0943921 chr16: 4322658-4323001 TFAP40.336101155 0.005641999 0.111386545 chr6: 32938355-32938493 HLA-DMA0.336336244 0.01336062 0.16167151 chr6: 108508504-108510013 NR2E10.336437613 0.012157358 0.155429477 chr12: 6756489-6756626 ACRBP0.336450652 0.009063847 0.137166781 chr11: 3400267-3400448 ZNF1950.336605687 0.002843888 0.081237547 chr1: 25558934-25558993 SYF20.336667727 0.004644165 0.10077894 chr7: 16872879-16873057 AGR20.336738631 2.81E−05 0.001591309 chr12: 118405880-118406788 KSR20.336775902 0.007835265 0.129133025 chr19: 56988640-56988770 ZNF6670.336884962 0.004098152 0.09575366 chr15: 83209176-83209208 RPS17L0.336885484 0.003539674 0.08867737 chr10: 5498550-5500426 NET10.33716755 0.005108136 0.10615454 chr17: 50237283-50237377 CA100.337244385 0.008810051 0.135263703 chr4: 159825617-159829201 FNIP20.33761486 0.01001205 0.143216183 chr5: 159855608-159855748 PTTG10.337619827 0.012232275 0.155522345 chr14: 36982316-36982990 SFTA30.337685044 0.009064788 0.137166781 chr9: 140194082-140196703 NRARP0.337748136 0.00700953 0.121921113 chr9: 104499562-104500862 GRIN3A0.337777935 0.003309214 0.085620014 chr9: 125084818-125085743 MRRF0.338049105 0.001250772 0.056511886 chr3: 167196633-167196792 SERPINI20.338488624 0.002335643 0.075350427 chr5: 98134164-98134347 RGMB0.338500085 0 0 chr17: 6920575-6920844 AC040977.1 0.33861797 0.0056123060.111134243 chr5: 154393314-154397692 KIF4B 0.33863313 0.0061241030.116167412 chr1: 145440852-145442635 TXNIP 0.33868063 0.0094497840.140634887 chr2: 113332423-113334673 POLR1B 0.338711651 0.0055640220.110932307 chr5: 1886975-1887350 IRX4 0.338712821 0.0029239330.082464901 chr2: 74729793-74732192 LBX2 0.338737246 0.0100631390.14338159 chr3: 138663065-138665982 FOXL2 0.33877365 0.0050171290.104742652 chr9: 88897292-88897676 ISCA1 0.339022749 0.0065598480.1185295 chr10: 98273267-98273675 TLL2 0.339042421 0.0036730760.091389151 chr2: 30862982-30867091 LCLAT1 0.339179902 0.0062997650.116920758 chr3: 197682620-197683481 RPL35A 0.33923522 0.0022470570.074896868 chr5: 140571941-140575215 PCDHB10 0.339319919 0.0049911150.104560114 chr6: 3982908-3984372 AL138831.1 0.339526883 0.0026394580.078334109 chr5: 171221568-171221602 C5orf50 0.339540771 0.0047669590.101816018 chr4: 76911848-76912115 SDAD1 0.339847696 0.0041625160.095871025 chr1: 92852567-92853730 RPAP2 0.340299513 0.003464150.087293121 chr17: 45899031-45899200 OSBPL7 0.34043401 0 0 chr16:81110740-81110818 C16orf46 0.340560273 0.00461508 0.10049394 chr19:55325296-55325972 KIR2DL4 0.340589063 0.002577114 0.077883735 chr5:114598408-114598569 PGGT1B 0.340742067 0.003243526 0.085503862 chr6:37225338-37225931 TMEM217 0.34102065 0.005320913 0.109004718 chr9:131456919-131458679 SET 0.34104979 0.00334917 0.086040971 chr7:130144779-130146133 MEST 0.341209576 0.002501724 0.076926292 chr1:32798617-32799236 HDAC1 0.341243395 0.008437076 0.133216661 chr7:117068123-117068177 ASZ1 0.341268169 0.018375867 0.183687882 chr1:166818174-166825581 POGK 0.341341081 0.002180119 0.074896868 chr3:169801692-169803191 GPR160 0.341411568 0 0 chr1: 173793699-173793858CENPL 0.341600458 0.004386422 0.098116492 chr9: 37356831-37358146 ZCCHC70.341832318 0.002878016 0.081933244 chr6: 153452258-153452384 RGS170.341997405 0.007479401 0.126251813 chr19: 2877270-2878501 ZNF5560.342151748 0.009710946 0.142148692 chr6: 150292504-150294844 ULBP10.342179031 0.007550635 0.126866028 chr1: 25824754-25826700 TMEM570.342284881 0.004046878 0.095335211 chr13: 26594025-26599989 ATP8A20.342473022 0.004835519 0.102307014 chr19: 12551725-12551926 ZNF4430.342588553 0.00297085 0.083014679 chr1: 146253037-146253110 WI2-0.342683663 0.012131595 0.155429477 3658N16.1 chr16: 18473011-18473188RP11- 0.342756738 0.007019189 0.121921113 1212A22.4 chr6:74233169-74233520 EEF1A1 0.342860281 0.003454471 0.087293121 chr2:102003478-102004057 CREG2 0.342980433 0.007909977 0.129431455 chr5:113831591-113832321 KCNN2 0.343097059 0.004322128 0.097640305 chr22:24125597-24126503 MMP11 0.343244705 0.006555426 0.1185295 chr22:38878500-38879452 KDELR3 0.343585262 0.005483917 0.109968839 chr14:64108016-64108125 WDR89 0.343869473 0.002621089 0.078272928 chr14:20825209-20826063 PARP2 0.34415271 0.009261923 0.139028346 chr8:42229080-42229326 POLB 0.344522366 0.008229294 0.132039458 chr12:110318076-110318293 GLTP 0.344549419 0.004690493 0.101059823 chr11:114320567-114321001 REXO2 0.344608407 0.007037485 0.122083904 chr11:132204939-132206716 NTM 0.344711378 0.005128034 0.106446266 chr19:58513763-58514717 ZNF606 0.344730774 0.003193862 0.085052362 chr10:12291579-12292588 CDC123 0.344789304 0.005742969 0.112400084 chr1:40758116-40759856 ZMPSTE24 0.345388616 0.00276453 0.080210303 chr12:53873189-53874945 PCBP2 0.345510005 0.00245255 0.07690982 chr11:4673715-4676718 OR51E1 0.345933376 0.003329808 0.085908111 chr1:43727512-43727589 EBNA1BP2 0.346047624 0.002367912 0.075986532 chr12:104359293-104359486 C12orf73 0.346225796 0.003975695 0.094764506 chr3:52029746-52029958 RPL29 0.346304272 0 0 chr19: 34302695-34306668 KCTD150.346487607 0.007147226 0.123047454 chr12: 102224336-102224716 GNPTAB0.346582993 0.002656535 0.078584121 chr1: 186282812-186283694 PRG40.347040363 0.001203172 0.054952728 chr20: 57485737-57486247 GNAS0.347157354 0.011944047 0.155429477 chr5: 72875701-72877794 UTP150.347177955 0 0 chr19: 1652298-1652326 TCF3 0.347341283 0.0032298550.085267223 chr8: 17104183-17104387 CNOT7 0.347410862 0.0036809220.091459073 chr4: 88312012-88312538 HSD17B11 0.347520476 0.0084547010.133216661 chr16: 67418772-67419106 LRRC36 0.347808564 0.0059346160.114006188 chr12: 70747608-70748773 CNOT2 0.348186738 0.0012731570.057173139 chr1: 52552383-52556388 BTF3L4 0.348370433 0.0026806230.078783422 chr17: 36294031-36294915 TBC1D3F 0.34873563 0.0026672890.078646054 chr22: 31363051-31364284 MORC2 0.348951739 0.0037507850.092052993 chr15: 52356098-52358462 MAPK6 0.34926453 0.0074104280.125555604 chr10: 50970284-50970425 OGDHL 0.349324408 0.005101690.106142027 chr6: 7417563-7418270 RIOK1 0.349666416 0.0072179730.12367929 chr12: 69783926-69784576 YEATS4 0.350000562 0.0081416070.131445347 chr13: 100622380-100624163 ZIC5 0.35012692 0.0082959580.132523738 chr9: 95244574-95244788 ASPN 0.350256133 0.0037592810.092052993 chr8: 101965496-101965616 YWHAZ 0.350510592 0.0057469750.112400084 chr20: 55840760-55841685 BMP7 0.350559373 0.0022609210.074896868 chr2: 47614696-47614740 EPCAM 0.350697329 0.0050884620.105988221 chr9: 139304779-139305061 SDCCAG3 0.350723691 0.0030542330.083821279 chr16: 332614-333003 ARHGDIG 0.350753346 0.0100062960.143216183 chr19: 19007369-19007488 LASS1 0.351329035 0.0103455170.145135442 chr9: 33917015-33920402 UBE2R2 0.351623699 0.0032059540.085084821 chr10: 33625122-33625190 NRP1 0.351650511 0.0001500140.008357973 chr4: 70079719-70080449 UGT2B11 0.351862854 0.0077413520.128531382 chr7: 99679923-99680171 ZNF3 0.352255056 0.0100140150.143216183 chr17: 40169357-40169715 DNAJC7 0.352324455 0.0015357380.065020053 chr6: 88376735-88377169 ORC3 0.352508512 0 0 chr1:2564304-2564481 MMEL1 0.352661402 0 0 chr17: 74944721-74946465 MGAT5B0.352666207 0.004035915 0.095200415 chr19: 52511393-52511483 ZNF6150.352758492 0.000854457 0.042519208 chr12: 54678041-54680872 HNRNPA10.352793166 0 0 chr21: 45079266-45079374 HSF2BP 0.352847214 0.0038363720.093530226 chr6: 76425100-76427997 SENP6 0.352949584 0.0020514730.074404864 chr8: 86129188-86129387 E2F5 0.352950312 0.0028632130.081639789 chr16: 19716437-19716880 C16orf62 0.353016377 0 0 chr1:148025760-148025863 NBPF14 0.353092408 0.004067093 0.09564239 chr7:155255065-155257526 EN2 0.353146057 0.007860271 0.129133025 chr14:70826235-70826444 COX16 0.353343863 0.002633087 0.078272928 chr5:140588268-140591696 PCDHB12 0.353452742 0.002137676 0.074896868 chr6:97345541-97345757 NDUFAF4 0.353576318 0.000829729 0.041516184 chr19:21560190-21562104 ZNF738 0.3536571 0.005514988 0.110317975 chr5:140557370-140560081 PCDHB8 0.353698505 0.00831499 0.13259453 chr4:55161291-55161439 FIP1L1 0.353817549 0.004681278 0.10098106 chr17:79771349-79771889 GCGR 0.354035638 0.005445589 0.109898029 chr19:52793318-52795977 ZNF766 0.354073875 0.002226165 0.074896868 chr1:63788729-63790797 FOXD3 0.354149363 0.005405168 0.109447113 chr1:147954634-147955419 PPIAL4A 0.354222847 0.002675456 0.078759014 chr12:122496997-122499948 BCL7A 0.354825754 0.002231741 0.074896868 chr9:123605014-123605229 PSMD5 0.355144141 0 0 chr2: 233412778-233415226TIGD1 0.355197399 0.004022874 0.095037797 chr22: 49246569-49246724FAM19A5 0.355373328 0.00336784 0.086049007 chr17: 41154888-41154956RPL27 0.355442918 0.002963896 0.083014679 chr12: 123741359-123742506C12orf65 0.355530218 0.013002282 0.159180228 chr6: 31937586-31940069DOM3Z 0.355568549 0.006009592 0.114897067 chr17: 5322673-5323000 NUP880.355910655 0.002129205 0.074896868 chr8: 26227649-26230196 PPP2R2A0.356005328 0.00272447 0.079641256 chr2: 74734702-74735707 PCGF10.356137025 0.006485052 0.118025771 chr10: 70968355-70968855 SUPV3L10.35616511 0 0 chrX: 70519791-70521018 NONO 0.35629128 0.0039652690.094764506 chr2: 44547337-44548633 SLC3A1 0.356342942 0.0134729250.162218034 chr7: 87536502-87538856 DBF4 0.356363925 0.0061377410.116167412 chr19: 37019120-37019562 ZNF260 0.356458224 0.0027254930.079641256 chr1: 149899617-149900236 SF3B4 0.356570693 0.0028274740.081130196 chr4: 83822235-83822319 SEC31A 0.35704326 0.0033602740.086049007 chr8: 19615360-19615540 CSGALNACT1 0.357581398 0 0 chr6:44221225-44221620 HSP90AB1 0.357638149 0.004764199 0.101816018 chr8:54934622-54935089 TCEA1 0.357638989 0.003470001 0.087293121 chr4:13485699-13485989 RAB28 0.358225721 0.00029466 0.015975864 chr10:61665879-61666414 CCDC6 0.358410884 0.004770436 0.101816018 chr15:82939013-82939159 RP13-98N21.1 0.358524403 0.003390575 0.086368012 chr5:170837530-170838141 NPM1 0.358661212 0.003112663 0.084283617 chr5:138665033-138667360 MATR3 0.358905176 0 0 chr1: 150443036-150449042RPRD2 0.358931012 0.001044122 0.049906291 chr19: 39303481-39303740LGALS4 0.359501829 0.002800501 0.080691396 chr7: 143002032-143004789CASP2 0.359779958 0.0052784 0.108821635 chr14: 64804615-64805317AL161756.1 0.360196944 0.001852672 0.072262867 chr17: 44833167-44834830NSF 0.360685738 0.004164634 0.095871025 chr11: 114284677-114284925 RBM70.360737625 0 0 chr2: 180725827-180726232 ZNF385B 0.3607536890.000458772 0.024364569 chr19: 51587392-51587502 KLK14 0.3612599010.009570729 0.141580566 chr19: 52868950-52870375 ZNF610 0.3612913890.001739732 0.070219452 chr14: 21737456-21737638 HNRNPC 0.3614779270.002287559 0.074896868 chr11: 117155801-117157161 RNF214 0.3618476210.00250308 0.076926292 chr13: 79979835-79980612 RBM26 0.362064040.00677961 0.120633891 chr5: 32601110-32604185 SUB1 0.362303909 0 0chr6: 53787432-53788919 LRRC1 0.362759243 0.001706266 0.069486359 chr11:22644078-22647387 FANCF 0.363489573 0 0 chr20: 52844491-52844591 PFDN40.363560498 0 0 chr6: 30613671-30614600 ATAT1 0.363580156 0.0038985380.094210495 chr16: 70605575-70608820 SF3B3 0.363659853 0.0085888330.134075072 chr16: 3355211-3355645 TIGD7 0.363725026 0 0 chr1:161135146-161135513 USP21 0.363771581 0.002323203 0.075082439 chr8:101733618-101735037 PABPC1 0.364174471 0.002118261 0.074896868 chr1:151688094-151689290 CELF3 0.364376964 0.002952999 0.083014679 chr9:133376362-133376661 ASS1 0.364697462 0.00725575 0.124092447 chr12:3048476-3050306 TULP3 0.364753258 0.006132467 0.116167412 chr4:111120255-111120355 ELOVL6 0.364868424 0.003051244 0.083821279 chr9:19378705-19380252 RPS6 0.365038972 0.002300966 0.074896868 chr10:121302101-121302220 RGS10 0.365192 0.002278591 0.074896868 chr16:277240-279462 LUC7L 0.365306003 0.003898555 0.094210495 chr19:24309055-24312643 ZNF254 0.365391007 0.00247424 0.076926292 chrX:152241317-152243401 AC152006.1 0.365477178 0.002089412 0.074557938 chr1:116609639-116612675 SLC22A15 0.365617395 0.005365482 0.109252525 chr15:69113036-69113236 ANP32A 0.366537633 0.002497996 0.076926292 chr11:6463716-6463847 HPX 0.36658236 0.003082241 0.084000815 chr17:4269565-4269969 UBE2G1 0.366624907 0 0 chr17: 30228554-30228731 UTP60.366824192 0.003624029 0.09052543 chr5: 178157556-178157703 ZNF354A0.367356176 0.002058499 0.074404864 chr14: 21464685-21465189 METTL170.367400305 0.002197521 0.074896868 chr1: 144828540-144830302 NBPF90.3679992 0.000828298 0.041516184 chr16: 3284635-3285456 ZNF2000.368145566 0.004814693 0.102159863 chr19: 33078158-33078322 PDCD50.368297261 0.004138572 0.095871025 chr1: 17766040-17766220 RCC20.36830465 0.006298625 0.116920758 chr22: 31740317-31742218 PATZ10.368414717 0 0 chr4: 96075698-96079599 BMPR1B 0.368570648 0 0 chr2:190339938-190340291 WDR75 0.368575508 0.001803079 0.071315614 chr15:52970768-52970820 KIAA1370 0.369520608 0.001991434 0.07433842 chr3:62359972-62359999 FEZF2 0.370011496 0.006297319 0.116920758 chr14:36789665-36789882 MBIP 0.370390986 0.002395341 0.076596085 chr9:131303380-131304567 GLE1 0.370432615 0.001207478 0.054952728 chr19:36726560-36729673 ZNF146 0.37076253 0.001797055 0.071315614 chr11:76731317-76737841 ACER3 0.371547935 0.002473745 0.076926292 chr5:44816544-44820530 MRPS30 0.372171618 0.001169204 0.054060041 chr20:50418817-50419014 SALL4 0.372219721 0.002515478 0.077005838 chr2:175113179-175113426 OLA1 0.372322556 0 0 chr11: 43876693-43878167HSD17B12 0.372729256 0.002281533 0.074896868 chr6: 111214678-111216916AMD1 0.372775014 0 0 chr2: 44999174-44999731 CAMKMT 0.3727821370.002908212 0.08228265 chr17: 30380284-30380517 LRRC37B 0.3740339790.002518387 0.077005838 chr14: 91883974-91884152 CCDC88C 0.3746429630.000670737 0.034807417 chr1: 85514078-85514182 MCOLN3 0.3746846250.003969808 0.094764506 chr11: 26744853-26744974 SLC5A12 0.3751890640.010525668 0.146272153 chr3: 52089865-52090566 DUSP7 0.3752034470.002453789 0.07690982 chr11: 102340904-102341115 TMEM123 0.3757217110.00219416 0.074896868 chr6: 27368071-27371683 ZNF391 0.375903341 0 0chr7: 19156293-19157295 TWIST1 0.376075851 0.000868692 0.043055081 chrX:129063311-129063737 UTP14A 0.376243265 0.002051346 0.074404864 chr21:18965469-18965897 CXADR 0.377652362 0 0 chr5: 68665483-68665840 TAF90.37769513 0.00220028 0.074896868 chr7: 149470196-149470568 ZNF4670.377842565 0.002987109 0.083076103 chr14: 89088611-89088615 ZC3H140.377843839 0 0 chr6: 137112847-137113656 MAP3K5 0.378372715 0.0039243030.0943921 chr1: 155707947-155708803 DAP3 0.378584615 0 0 chr12:118500157-118500235 WSB2 0.378701761 0.003285179 0.085620014 chr12:122985186-122985518 ZCCHC8 0.37906625 0 0 chr20: 13797763-13799067C20orf7 0.379646265 0.002733521 0.079693317 chr20: 20693017-20693266RALGAPA2 0.379953096 0.000392922 0.02099011 chr17: 27940371-27941779ANKRD13B 0.379965854 0 0 chr2: 24991089-24993571 NCOA1 0.3800496810.003108189 0.084283617 chr1: 2706067-2706280 TTC34 0.3801316080.00112532 0.053024689 chr11: 61136068-61136683 TMEM138 0.3803824770.002431464 0.07683164 chr5: 72801016-72801460 BTF3 0.3806322570.004553657 0.099768482 chr12: 26277650-26278060 BHLHE41 0.3806495570.000869967 0.043055081 chr11: 77348634-77348850 CLNS1A 0.381389378 0 0chr11: 64940653-64940715 SPDYC 0.381489194 0.001862618 0.072287892 chr1:169555466-169555826 F5 0.382149137 0 0 chr1: 113212613-113214241 CAPZA10.382444099 0 0 chr11: 118888070-118889401 RPS25 0.38247485 0 0 chr6:119228566-119230332 ASF1A 0.382887636 0 0 chr9: 96082648-96082854 WNK20.383066155 0.002147218 0.074896868 chr16: 48419114-48419361 SIAH10.38346374 0 0 chr6: 117252493-117253326 RFX6 0.383666724 0.0031374720.08454882 chr5: 140890513-140892546 PCDHGA1 0.384828032 0 0 chr1:203821268-203823252 ZC3H11A 0.385182686 0 0 chr12: 57125273-57125412NACA 0.386358061 0.002030959 0.074404864 chr19: 11849631-11849824 ZNF8230.386599542 0 0 chr22: 41255552-41258130 DNAJB7 0.386599867 0 0 chr9:86595417-86595569 HNRNPK 0.38694272 0 0 chr12: 21391912-21392180 SLCO1B10.38730007 0 0 chr4: 165878099-165880274 C4orf39 0.387654409 0 0 chr13:53216540-53217919 HNRNPA1L2 0.387659039 0.003340795 0.085969228 chr7:16921567-16921611 AGR3 0.387702629 0.003578066 0.089515727 chr10:27035261-27035727 PDSS1 0.388612797 0.002981744 0.083076103 chr12:15114470-15114662 ARHGDIB 0.388654077 0 0 chr9: 74525549-74525847FAM108B1 0.389098607 0 0 chr4: 77996624-77997158 CCNI 0.389315949 0 0chr22: 29137756-29138410 CHEK2 0.389761154 0.00049489 0.026054161 chr4:69696317-69696914 UGT2B10 0.390049265 0.00315215 0.08468855 chr4:44700560-44702943 GUF1 0.390286785 0.001037899 0.049739741 chr4:169931098-169931426 CBR4 0.390480296 0.002223282 0.074896868 chr1:46158875-46160115 TMEM69 0.390570946 0.000653249 0.033997013 chr19:11494768-11495018 EPOR 0.390666769 0.001169718 0.054060041 chr6:32151657-32152101 AGER 0.39120754 0.002536025 0.077155474 chrX:51238802-51239448 NUDT11 0.392382255 0 0 chr11: 1481729-1483919 BRSK20.392392838 0.001425388 0.061936163 chr10: 35927176-35930362 FZD80.392659985 0.002373224 0.07602269 chr5: 34924951-34926101 BRIX10.392764346 0.000257339 0.014078459 chr11: 108810972-108811657 DDX100.393686876 0 0 chr6: 151422661-151423023 MTHFD1L 0.393780109 0 0 chr5:179498455-179499118 RNF130 0.39413346 0.002300383 0.074896868 chr2:207653542-207657233 FASTKD2 0.395080106 0.002995917 0.083076103 chr1:32801547-32801980 MARCKSL1 0.395222571 0 0 chr15: 58073773-58074960GRINL1A 0.395317713 0 0 chr5: 150080493-150080669 RBM22 0.3953925280.00249879 0.076926292 chr11: 58345458-58345693 LPXN 0.3954282970.003088638 0.084000815 chr1: 167757056-167761156 MPZL1 0.395807291 0 0chr1: 154531383-154531504 UBE2Q1 0.395931922 0 0 chr21:27107163-27107984 ATP5J 0.395993559 0.001203617 0.054952728 chr1:84963111-84963473 RPF1 0.396095665 0 0 chr14: 20925149-20925933 APEX10.396178148 0.001190996 0.05490369 chr6: 116914142-116918838 RWDD10.396503437 0.002228124 0.074896868 chr9: 33798853-33799230 PRSS30.397409769 0 0 chr9: 74597572-74600970 C9orf85 0.397495381 0 0 chr11:62507447-62507756 TTC9C 0.397920759 0 0 chr6: 47009926-47010099 GPR1100.397964341 0.002809976 0.080755689 chr1: 236385090-236385165 GPR137B0.398121433 0.002838645 0.081237547 chr6: 107979410-107981357 SOBP0.39849222 0 0 chr1: 151220338-151222012 PIP5K1A 0.398670482 0.0015784290.066031038 chr12: 21242841-21243179 RP11-545J16.1 0.3986879340.002064621 0.074404864 chr1: 154243356-154243986 UBAP2L 0.3987639560.001640837 0.067674286 chr2: 9613044-9613230 CPSF3 0.3988396770.000818676 0.04119004 chr6: 28097207-28097860 ZSCAN16 0.399313964 0 0chr5: 68849396-68853931 OCLN 0.399353915 0 0 chr1: 183567145-183567381SMG7 0.399418476 0 0 chr12: 50492729-50494495 SMARCD1 0.399921615 0 0chr10: 33171620-33171802 C10orf68 0.39996233 0 0 chr7: 23571407-23571660TRA2A 0.400855902 0.001909912 0.07290082 chr1: 2520848-2522908 C1orf930.401674406 0.000832687 0.041549723 chr21: 33103975-33104431 SCAF40.401930251 0.00367158 0.091389151 chr6: 30530165-30531500 PRR30.402082178 0.003156645 0.08468855 chr2: 223520734-223521056 FARSB0.402157653 0.001309609 0.058443307 chr12: 96437066-96437298 LTA4H0.402185173 0 0 chr5: 140041763-140042064 IK 0.402703343 0.0017749870.071167982 chr1: 155248165-155248282 CLK2 0.40304566 0.0029432210.082880196 chr10: 71871273-71872032 H2AFY2 0.403191879 0 0 chr13:103491900-103493885 BIVM 0.40403719 0.000414281 0.022066226 chr1:228353174-228353213 C1orf148 0.404051637 0.000953353 0.046515259 chr2:42719976-42721237 KCNG3 0.404235536 0.0011298 0.053024689 chr1:54879028-54879152 SSBP3 0.404739966 0.001387273 0.060862399 chr3:195310748-195311076 APOD 0.405410563 0 0 chr9: 129458572-129463311 LMX1B0.406246618 0.002026027 0.074404864 chr11: 93583577-93583697 C11orf900.406962716 0.002608771 0.078272928 chr12: 56693943-56694176 CS0.407050318 0 0 chr22: 44258093-44258398 SULT4A1 0.407538876 0 0 chr19:14201749-14201848 SAMD1 0.407614144 0 0 chr17: 44632896-44633016LRRC37A2 0.40823187 0.00107377 0.051188688 chr7: 33148832-33149013 RP90.408861449 0 0 chr19: 20046830-20046860 ZNF93 0.409274151 0 0 chr15:77241410-77242601 RCN2 0.409441008 0.001415528 0.061655257 chr1:26233278-26233482 STMN1 0.409501544 0 0 chr1: 222886085-222886552 AIDA0.410481766 0.00279499 0.080691396 chr13: 100637576-100639018 ZIC20.410515198 0.001274851 0.057173139 chr2: 181940922-181941312 UBE2E30.410818774 0.002071907 0.074404864 chr8: 97273728-97273838 MTERFD10.411514119 0 0 chr6: 80751835-80752244 TTK 0.412567895 0.0007829330.039721802 chr11: 49229843-49230222 FOLH1 0.412864835 0.0009150020.045038408 chr11: 18127453-18127638 SAAL1 0.412967343 0.0017161010.069576817 chr2: 74718607-74722013 TTC31 0.413386439 0.0023207750.075082439 chr2: 172952730-172954405 DLX1 0.413626042 0 0 chr1:156051335-156051789 MEX3A 0.414113678 0 0 chr20: 45985400-45985567ZMYND8 0.414360157 0.003386848 0.086368012 chr6: 20490398-20493945 E2F30.414889711 0 0 chr9: 17502548-17503921 CNTLN 0.415096245 0 0 chr11:125933120-125933230 CDON 0.415241654 0.003399941 0.086368012 chr16:1374730-1377019 UBE2I 0.415614971 0.000805294 0.04062931 chr4:85418711-85419603 NKX6-1 0.415770608 0.002969533 0.083014679 chr1:2345035-2345236 PEX10 0.415818061 0.00226998 0.074896868 chr13:37583320-37583750 EXOSC8 0.41616237 0 0 chr6: 114332294-114332472 HDAC20.41634724 0 0 chr11: 94730187-94732682 KDM4D 0.416396892 0 0 chr7:96639107-96640351 DLX6 0.416500311 0 0 chr1: 43316593-43318148 ZNF6910.417052551 0 0 chr6: 30620387-30620987 C6orf136 0.417479864 0 0 chr1:38455541-38456593 SF3A3 0.419671206 0 0 chr16: 3450944-3451030 ZNF4340.421275822 0 0 chr2: 27886195-27886676 SUPT7L 0.421878368 0 0 chr3:131221573-131221827 MRPL3 0.422205914 0.004302763 0.097323884 chr6:117890782-117891021 DCBLD1 0.422518501 0 0 chr6: 37298819-37300746TBC1D22B 0.422672614 0 0 chr19: 52531494-52531680 ZNF614 0.4228087850.001307515 0.058443307 chr12: 76478346-76478813 NAP1L1 0.423706864 0 0chr6: 110797724-110797844 SLC22A16 0.424337101 0 0 chr17:38290531-38293040 MSL1 0.425415614 0 0 chr2: 71192087-71192555 ATP6V1B10.425997989 0 0 chr1: 236645566-236648026 EDARADD 0.426385524 0 0 chr1:90398625-90402170 LRRC8D 0.4277395 0 0 chr15: 34880591-34880704 GOLGA8A0.428326543 0.001214634 0.055015953 chr17: 27277912-27278789 PHF120.428389454 0.001210213 0.054952728 chr7: 50632981-50633154 DDC0.428397647 0 0 chr10: 122348814-122349367 PPAPDC1A 0.4285736340.002188707 0.074896868 chr12: 54428061-54429145 HOXC5 0.4294140560.001786691 0.071315614 chr3: 63849179-63849579 THOC7 0.429484227 0 0chr17: 57351011-57353322 GDPD1 0.430283967 0 0 chr19: 11529921-11530018RGL3 0.432861793 7.75E−05 0.004357466 chr12: 54423414-54424607 HOXC60.432933362 0.001968332 0.074231845 chr6: 107372260-107372546 C6orf2030.433507583 0.000780773 0.039721802 chr17: 27169675-27169841 C17orf630.43537005 0 0 chr12: 2113366-2113701 DCP1B 0.438106424 0.0027575570.080136814 chr20: 62168437-62168723 PTK6 0.438444953 0.0024330760.07683164 chr20: 524315-524482 CSNK2A1 0.438596671 0 0 chr2:40006253-40006407 THUMPD2 0.438989821 0 0 chr1: 38061359-38061540 GNL20.439023194 0 0 chr7: 40899914-40900362 C7orf10 0.439295183 0.0013142190.058505314 chr12: 54448633-54449814 HOXC4 0.440488904 0.001622940.067166971 chr2: 86422460-86422893 IMMT 0.440753615 0.0002512540.013818534 chr4: 147442769-147443123 SLC10A7 0.441806672 0.0011646030.054060041 chr1: 145368440-145370303 NBPF10 0.441846603 0 0 chr6:46669594-46672056 TDRD6 0.442466815 0 0 chr5: 136933886-136934068 SPOCK10.443225182 0 0 chr4: 39529418-39529931 UGDH 0.444185722 0 0 chr8:145979576-145981802 ZNF251 0.445163073 0.001145009 0.05346221 chr11:381668-382116 B4GALNT4 0.445270209 0 0 chr5: 68737358-68740157 MARVELD20.446183422 0.001432367 0.06194304 chr1: 150325308-150325671 PRPF30.447239122 0 0 chr3: 53845139-53846490 CACNA1D 0.448853672 0 0 chr9:126030714-126030855 STRBP 0.449208753 0 0 chrX: 109683117-109683461AMMECR1 0.449831614 0.003696425 0.091617209 chr5: 74072428-74072737 NSA20.450170336 0.000888381 0.043846937 chr19: 19654489-19657468 CILP20.451206343 0 0 chr22: 19770836-19771116 TBX1 0.45229799 0.001332810.059043466 chr16: 11945264-11945442 RSL1D1 0.453363354 0 0 chr12:56509926-56509935 PA2G4 0.453629094 0.001682554 0.068829349 chr11:18063910-18063973 TPH1 0.454146123 0.001759224 0.070831349 chr6:111137010-111137161 CDK19 0.461218971 0 0 chr5: 11903928-11904155 CTNND20.46164781 0 0 chr9: 23825803-23826335 ELAVL2 0.461847559 0.0018789070.072455602 chr5: 137910926-137911133 HSPA9 0.462177989 0 0 chr16:15224943-15225458 PKD1P6 0.463922149 0 0 chr10: 115991244-115992063TDRD1 0.464073889 0 0 chr11: 49059029-49059579 AC084851.1 0.4647034570.000995607 0.048093643 chrX: 135962755-135962939 RBMX 0.467663273 0 0chr15: 74005274-74006859 CD276 0.469036908 0.001399893 0.061268074 chr6:76624529-76629254 MYO6 0.472241272 0 0 chr6: 105627707-105627870 POPDC30.474183404 0 0 chr1: 224517772-224518089 NVL 0.474352541 0.0002175760.012048295 chr9: 93405033-93405386 DIRAS2 0.476231667 0 0 chr20:1373477-1373806 FKBP1A 0.477529689 0 0 chr9: 131262345-131263239 ODF20.479887989 0 0 chr10: 124923335-124924886 BUB3 0.481360778 0.0007098250.03641962 chr5: 133304136-133304478 C5orf15 0.481540922 0 0 chr1:84855461-84855640 SAMD13 0.483533428 0 0 chr5: 79865972-79866307ANKRD34B 0.48535555 0 0 chr3: 132004083-132004254 CPNE4 0.487204732 0 0chr1: 40783259-40783488 COL9A2 0.488099327 0 0 chr6: 111346605-111347303RPF2 0.488404844 0 0 chr12: 82152992-82153332 PPFIA2 0.488405043 0 0chr1: 76076724-76076801 SLC44A5 0.48908972 0.00026347 0.014369004 chr11:94965320-94965705 SESN3 0.490557941 0 0 chr5: 102611597-102614361C5orf30 0.50386609 0 0 chr1: 166845396-166845564 TADA1 0.508490879 0 0chr6: 28200339-28201260 ZNF193 0.511690319 0 0 chr4: 122617735-122618268ANXA5 0.516661902 0 0 chr2: 203630168-203634480 FAM117B 0.517778257 0 0chr15: 82554954-82555104 EFTUD1 0.51899271 0 0 chr6: 46703286-46703430PLA2G7 0.519577791 0 0 chr6: 24785865-24786327 GMNN 0.522285573 0 0chr3: 175520792-175523428 NAALADL2 0.531051532 0 0 chr1:70587462-70589164 LRRC7 0.531438025 0 0 chr6: 38997880-38998301 DNAH80.533275843 0 0 chr1: 31769457-31769662 SNRNP40 0.533891931 0 0 chr3:3886047-3889387 LRRN1 0.539082031 0 0 chr17: 4545517-4545589 ALOX150.542179201 0 0 chr18: 55143668-55158530 ONECUT2 0.543914583 0 0 chr18:63547636-63552376 CDH7 0.547130694 0 0 chr11: 129728468-129729898TMEM45B 0.551304803 0 0 chr17: 38821255-38821393 SMARCE1 0.554810297 0 0chr6: 107436293-107436473 BEND3 0.555214105 0 0 chr1:180991774-180992047 STX6 0.555781993 0.001806154 0.071315614 chr9:114361882-114362135 PTGR1 0.556369465 0 0 chr3: 193855471-193856521 HES10.556473721 0 0 chr6: 38670746-38670917 GLO1 0.559523889 0 0 chr2:71159896-71160576 VAX2 0.561327888 0 0 chr8: 136668468-136668965 KHDRBS30.563811465 0 0 chr9: 79634570-79635869 FOXB2 0.583315396 0 0 chr1:31712340-31712401 NKAIN1 0.590810474 0 0 chr6: 107780193-107780768 PDSS20.595945426 0 0 chr2: 181780999-181782519 SCHLAP1 1 0 0 locus pglobalqglobal prank padj chr12: 57180908-57181574 2.21E−06 0.0028939940.000660684 0.001483863 chr10: 100995269-100995619 4.25E−06 0.0032610460.000935969 0.000935969 chr9: 4585311-4587469 4.60E−06 0.0032610460.001046083 0.001046083 chr12: 104234726-104234975 4.88E−06 0.0032610460.001266311 0.001266311 chr1: 85358698-85358896 5.53E−06 0.0032610460.001541596 0.001541596 chr7: 12692212-12693228 6.48E−06 0.0036766170.00165171 0.00165171 chr1: 204328821-204329044 6.68E−06 0.0036768890.001706767 0.001706767 chr22: 31674282-31676066 8.12E−06 0.0040151990.001871937 0.001871937 chr16: 85121881-85127826 8.39E−06 0.0040151990.001926994 0.001926994 chr11: 126310080-126310239 8.40E−06 0.0040151990.001982051 0.001982051 chr2: 102855651-102856462 9.02E−06 0.0042010280.002037108 0.002037108 chr2: 100759172-100759201 9.27E−06 0.0042100110.002092165 0.002092165 chr3: 87039767-87040269 1.09E−05 0.0048103450.002257336 0.002257336 chr10: 106058885-106059616 1.52E−05 0.006416190.002202279 0.002202279 chr18: 78005159-78005429 1.56E−05 0.0064249420.00236745 0.00236745 chr5: 14692962-14699820 1.76E−05 0.0070849090.002422507 0.002422507 chr11: 124955849-124959131 1.97E−05 0.0072364610.002312393 0.002312393 chr11: 134134801-134135749 2.40E−05 0.0082311580.002587678 0.002587678 chr12: 104159806-104160505 2.45E−05 0.0082353580.002642735 0.002642735 chr13: 24462816-24463558 2.88E−05 0.0092228720.002807906 0.002807906 chr15: 89738457-89745591 2.89E−05 0.0092228720.003028134 0.003028134 chr16: 22295207-22297954 3.24E−05 0.0095571990.002862963 0.002862963 chr6: 159185526-159185908 3.32E−05 0.0095571990.002973077 0.002973077 chr2: 204399833-204400133 4.11E−05 0.0107185710.003248362 0.003248362 chr21: 35987058-35987441 4.13E−05 0.0107185710.003303419 0.003303419 chr2: 242089022-242089679 4.23E−05 0.010828720.003358476 0.003358476 chr1: 153603987-153604513 4.69E−05 0.0115200230.00346859 0.00346859 chr9: 77502739-77503010 5.03E−05 0.0121215450.003523647 0.003523647 chr5: 66458974-66465423 5.40E−05 0.0121215450.003578704 0.003578704 chr12: 112247346-112247782 5.50E−05 0.0121215450.003633761 0.003633761 chr20: 33460449-33460663 5.50E−05 0.0121215450.003688818 0.003688818 chr16: 84695183-84701292 6.03E−05 0.0127245350.004404559 0.004404559 chr5: 55218223-55218678 6.09E−05 0.0127245350.00401916 0.00401916 chrX: 63615219-63615333 6.18E−05 0.0127612830.004074217 0.004074217 chr16: 84538206-84538296 6.44E−05 0.0131270930.004129274 0.004129274 chrX: 18671551-18671749 6.50E−05 0.0131270930.004184331 0.004184331 chr10: 94050682-94050844 6.65E−05 0.01326860.004239388 0.004239388 chr18: 11908199-11908779 6.74E−05 0.0133139830.004294445 0.004294445 chr3: 189839991-189840226 7.07E−05 0.0137847920.0051203 0.0051203 chr1: 154321315-154323783 7.13E−05 0.0137847920.004349502 0.004349502 chr4: 100009839-100009952 7.21E−05 0.0137898350.004404559 0.004404559 chr2: 202028557-202029033 9.16E−05 0.0168041590.004514673 0.004514673 chr11: 130272233-130273133 9.42E−05 0.0169393910.00456973 0.00456973 chr4: 106924870-106925184 9.56E−05 0.0170264720.005395584 0.005395584 chr17: 53809031-53809482 9.71E−05 0.0170863510.004624787 0.004624787 chr18: 19102618-19102791 0.00010456 0.0179051640.004734901 0.004734901 chr7: 128461852-128462186 0.0001052830.017905164 0.004789958 0.004789958 chr4: 113206795-1132070590.000110766 0.018214263 0.004900072 0.004900072 chr13:111955337-111958084 0.000113277 0.018370082 0.005010186 0.005010186chr7: 103086544-103086624 0.000118707 0.018912891 0.0056158120.005615812 chr2: 199436579-199437305 0.000122153 0.019126366 0.00512030.0051203 chr7: 99526462-99527243 0.000124666 0.019242801 0.0051753560.005175356 chr17: 1613360-1613651 0.000126503 0.019242801 0.0056708690.005670869 chr11: 44640598-44641913 0.00013486 0.020077586 0.0053405270.005340527 chr11: 134094990-134095348 0.000136153 0.0201052870.005395584 0.005395584 chr1: 152297664-152297679 0.0001448670.020358172 0.005560755 0.005560755 chr18: 8406106-8406859 0.0001450.020358172 0.005615812 0.005615812 chr11: 74178676-74178774 0.0001457120.020358172 0.005725926 0.005725926 chr17: 7951703-7952452 0.0001503850.020596714 0.005780983 0.005780983 chr3: 49213037-49213918 0.0001505530.020596714 0.00583604 0.00583604 chr2: 219696460-219696809 0.0001508210.020596714 0.005891097 0.005891097 chr14: 23778024-23780968 0.0001623260.021533748 0.005946154 0.005946154 chr8: 11182824-11182938 0.0001667560.021533748 0.006331553 0.006331553 chr14: 77843278-77843396 0.0001741140.021961395 0.007763035 0.007763035 chr8: 22926263-22926692 0.0001981430.024649764 0.006221439 0.006221439 chr11: 118550247-1185503990.000206789 0.025550394 0.006276496 0.006276496 chr8: 22471420-224741700.000215369 0.025749707 0.006331553 0.006331553 chr14: 76668033-766691340.000215491 0.025749707 0.00638661 0.00638661 chr7: 83277743-832784790.00021898 0.025995608 0.006441667 0.006441667 chr8: 109095151-1090959130.000231367 0.027287785 0.006496724 0.006496724 chr6: 42931272-429316180.000243869 0.027410832 0.006661895 0.006661895 chr1: 24795475-247994660.00024945 0.027410832 0.006661895 0.006661895 chrX: 148713225-1487135680.000251178 0.027410832 0.006772009 0.006772009 chr6: 52860046-528601760.00025189 0.027410832 0.008974288 0.008974288 chr11: 4903048-49041130.000252001 0.027410832 0.008809117 0.008809117 chr20: 45362394-453649650.000253538 0.027410832 0.008809117 0.008809117 chr14: 21167513-211687610.00025544 0.027452953 0.008809117 0.008809117 chrX: 23783663-237845920.000269284 0.028436048 0.006992237 0.006992237 chr12: 22218054-222186080.00028048 0.029277918 0.008258548 0.008258548 chr13:114203739-114204542 0.0002876 0.029849598 0.008148434 0.008148434 chr7:127233551-127233665 0.000296624 0.030160322 0.007212465 0.007212465chr1: 168211738-168212378 0.000297236 0.030160322 0.0078731490.007873149 chr7: 80551580-80551675 0.000309825 0.030524412 0.0078180920.007818092 chr5: 149011544-149014531 0.000312739 0.0305244120.008974288 0.008974288 chr6: 125583979-125585553 0.0003143970.030524412 0.007377636 0.007377636 chr22: 39190072-39190148 0.000317630.030524412 0.007542807 0.007542807 chr14: 75201584-75203421 0.0003212890.030617528 0.007597864 0.007597864 chr4: 142133947-142134031 0.000321970.030617528 0.010185542 0.010185542 chr6: 159420466-1594212190.000327348 0.030966787 0.007652921 0.007652921 chr7:142637438-142637955 0.000329233 0.030983765 0.008423719 0.008423719chr1: 38019606-38019905 0.000356182 0.03317611 0.007763035 0.007763035chr12: 112590538-112591407 0.000369367 0.0338033 0.009084402 0.009084402chr8: 11643471-11644855 0.000381186 0.0338033 0.008699003 0.008699003chrX: 99986990-99987110 0.000382884 0.0338033 0.008093377 0.008093377chr1: 11865403-11866977 0.000384771 0.0338033 0.008203491 0.008203491chr17: 19578870-19580909 0.000386887 0.0338033 0.008258548 0.008258548chr1: 11322501-11322608 0.000388904 0.0338033 0.008313605 0.008313605chr22: 29449566-29453475 0.000393128 0.033840648 0.008368662 0.008368662chr6: 3157640-3157809 0.000399369 0.033903107 0.008423719 0.008423719chr17: 12893348-12894960 0.000403186 0.033903107 0.00858889 0.00858889chr1: 110888929-110889299 0.00040617 0.033963425 0.008643946 0.008643946chr7: 227553-229557 0.000407643 0.033963425 0.008699003 0.008699003chr21: 39288186-39288749 0.000413797 0.034004231 0.01040577 0.01040577chr13: 21635484-21635718 0.000415622 0.034004231 0.008809117 0.008809117chr3: 68981390-68981761 0.000421217 0.034068108 0.011561967 0.011561967chr17: 56032585-56032684 0.000423903 0.034068108 0.00930463 0.00930463chr11: 94861540-94865809 0.000425781 0.034068108 0.008919231 0.008919231chr9: 5339535-5339873 0.000433669 0.034246655 0.010846226 0.010846226chr8: 22291403-22291642 0.00045167 0.035043161 0.01222265 0.01222265chrX: 2799092-2800859 0.000454498 0.035043161 0.008974288 0.008974288chr5: 10649377-10650308 0.000458355 0.035043161 0.009029345 0.009029345chr3: 33138210-33138293 0.000460544 0.035043161 0.012057479 0.012057479chr17: 74639589-74639894 0.000462776 0.035043161 0.009139459 0.009139459chr4: 108871400-108874613 0.000462962 0.035043161 0.0091945160.009194516 chr13: 24476755-24476794 0.000463125 0.035043161 0.0092495730.009249573 chr2: 222438569-222438922 0.000463739 0.0350431610.012883334 0.012883334 chr7: 99573567-99573780 0.000464978 0.0350431610.011617024 0.011617024 chr11: 134188770-134189458 0.000473310.035377477 0.00930463 0.00930463 chr15: 90286522-90286868 0.0004812850.035534876 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All publications, patents, patent applications and accession numbersmentioned in the above specification are herein incorporated byreference in their entirety. Although the invention has been describedin connection with specific embodiments, it should be understood thatthe invention as claimed should not be unduly limited to such specificembodiments. Indeed, various modifications and variations of thedescribed compositions and methods of the invention will be apparent tothose of ordinary skill in the art and are intended to be within thescope of the following claims.

1.-272. (canceled)
 273. A system for analyzing a cancer, comprising: a.a probe set comprising a plurality of probes, wherein the plurality ofprobes comprises a sequence that hybridizes to at least a portion of oneor more target molecules selected from the group comprising PCAT,SChLAP-1, TU0011194, TU0019356, TU0024146, TU0009141, TU0062051,TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9; and b. a computer model oralgorithm for analyzing an expression level and/or expression profile ofa target molecule hybridized to the probe in a sample from a subjectsuffering from a cancer.
 274. The system claim 273, wherein PCAT isselected from the group comprising PCAT1, PCAT2, PCAT3, PCAT4, PCAT5,PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11, PCAT12, PCAT13, PCAT14,PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20, PCAT21, PCAT22, PCAT23,PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29, PCAT30, PCAT31, PCAT32,PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38, PCAT39, PCAT40, PCAT41,PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47, PCAT48, PCAT49, PCAT50,PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56, PCAT57, PCAT58, PCAT59,PCAT60, PCAT61, PCAT62, PCAT63, PCAT64, PCAT65, PCAT66, PCAT67, PCAT68,PCAT69, PCAT70, PCAT71, PCAT72, PCAT73, PCAT74, PCAT75, PCAT76, PCAT77,PCAT78, PCAT79, PCAT80, PCAT81, PCAT82, PCAT83, PCAT84, PCAT85, PCAT86,PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92, PCAT93, PCAT94, PCAT95,PCAT96, PCAT97, PCAT98, PCAT99, PCAT100, PCAT101, PCAT102, PCAT103,PCAT104, PCAT105, PCAT106, PCAT107, PCAT108, PCAT109, PCAT110, PCAT111,PCAT112, PCAT113, PCAT114, PCAT115, PCAT116, PCAT117, PCAT118, PCAT119,PCAT120, and PCAT121.
 275. The system of claim 273, further comprisingan electronic memory for capturing and storing an expression profile.276. The system of claim 273, further comprising a computer-processingdevice, optionally connected to a computer network.
 277. The system ofclaim 276, further comprising a software module executed by thecomputer-processing device to analyze an expression profile.
 278. Thesystem of claim 276, further comprising a software module executed bythe computer-processing device to compare the expression profile to astandard or control.
 279. The system of claim 276, further comprising asoftware module executed by the computer-processing device to determinethe expression level of the target.
 280. The system of claim 276,further comprising a software module executed by the computer-processingdevice to transmit an analysis of the expression profile to the subjector a medical professional treating the subject.
 281. The system of claim276, further comprising a software module executed by thecomputer-processing device to transmit a diagnosis or prognosis to thesubject or a medical professional treating the subject.
 282. The systemof claim 273, further comprising a machine to isolate the target or theprobe from the sample, a machine to sequence the target or the probe,and/or a machine to amplify the target or the probe.
 283. The system ofclaim 273, wherein the plurality of probes comprises a sequence thathybridizes to at least a portion of two or more target moleculesselected from the group comprising PCAT, SChLAP-1, TU0011194, TU0019356,TU0024146, TU0009141, TU0062051, TU0021861, M41, ENST-75, and SEQ IDNOs: 1-9.
 284. The system of claim 273, wherein the cancer is selectedfrom the group comprising prostate, lung, breast, and pancreatic cancer.285. The system of claim 273, wherein the plurality of probes comprisesa sequence that hybridizes to at least a portion of one or more targetmolecules selected from the group comprising and SEQ ID NOs: 1-9, PCAT1,PCAT14, PCAT43, PCAT 109, and SChLAP-1.
 286. The system of claim 285,wherein the cancer is a prostate cancer.
 287. The system of claim 273,wherein the plurality of probes comprises a sequence that hybridizes toat least a portion of one or more target molecules selected from thegroup comprising M41 and ENST-75.
 288. The system of claim 287, whereinthe cancer is a lung cancer.
 289. The system of claim 273, wherein theplurality of probes comprises a sequence that hybridizes to at least aportion of one or more target molecules selected from the groupcomprising TU0011194, TU0019356 and TU0024146.
 290. The system of claim288, wherein the cancer is a breast cancer or prostate.
 291. The systemof claim 273, wherein the plurality of probes is attached to one or moresolid supports.
 292. The system of claim 291, wherein the one or moresolid supports is a bead, array, microarray, well, plate, chip, or acombination thereof.